U.S. patent application number 12/376141 was filed with the patent office on 2009-12-24 for agonists of the sphingosine-1 phosphate receptor.
This patent application is currently assigned to PRAECIS PHARMACEUTICALS INCORPORATED. Invention is credited to Hongfeng Deng, Ghotas Evindar.
Application Number | 20090318389 12/376141 |
Document ID | / |
Family ID | 38896934 |
Filed Date | 2009-12-24 |
United States Patent
Application |
20090318389 |
Kind Code |
A1 |
Evindar; Ghotas ; et
al. |
December 24, 2009 |
AGONISTS OF THE SPHINGOSINE-1 PHOSPHATE RECEPTOR
Abstract
The invention provides compounds formulae I-III, their
preparation, and their use as pharmaceutically active
immunosuppressive agents for the treatment of autoimmune disorders,
organ transplant rejection, disorders associated with an activated
immune system, as well as other disorders modulated by lymphopenia
or SIP receptors.
Inventors: |
Evindar; Ghotas;
(Shrewsbury, MA) ; Deng; Hongfeng; (Acton,
MA) |
Correspondence
Address: |
GLAXOSMITHKLINE;CORPORATE INTELLECTUAL PROPERTY, MAI B482
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Assignee: |
PRAECIS PHARMACEUTICALS
INCORPORATED
Waltham
MA
|
Family ID: |
38896934 |
Appl. No.: |
12/376141 |
Filed: |
August 2, 2007 |
PCT Filed: |
August 2, 2007 |
PCT NO: |
PCT/US07/17384 |
371 Date: |
March 26, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60821432 |
Aug 4, 2006 |
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60821425 |
Aug 4, 2006 |
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60827941 |
Oct 3, 2006 |
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60827928 |
Oct 3, 2006 |
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Current U.S.
Class: |
514/92 ;
514/255.03; 514/365; 544/395; 548/119; 548/205 |
Current CPC
Class: |
A61P 25/28 20180101;
C07F 9/6539 20130101; C07D 233/64 20130101; C07D 241/04 20130101;
C07D 285/12 20130101; C07F 9/091 20130101; C07D 277/28 20130101;
C07C 323/41 20130101; C07F 9/6506 20130101; C07F 9/650952 20130101;
A61P 25/00 20180101; C07D 241/08 20130101; C07F 9/65395 20130101;
A61P 43/00 20180101; C07B 2200/07 20130101 |
Class at
Publication: |
514/92 ; 548/205;
514/365; 548/119; 544/395; 514/255.03 |
International
Class: |
A61K 31/675 20060101
A61K031/675; C07D 277/28 20060101 C07D277/28; A61K 31/426 20060101
A61K031/426; C07F 9/6539 20060101 C07F009/6539; C07D 241/04
20060101 C07D241/04; A61K 31/495 20060101 A61K031/495 |
Claims
1. A compound of formula I ##STR00166## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is halogen, cyano, alkyl,
aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroalkyl, --O-alkyl, --O-aryl, --O-heteroaryl, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, or dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl; R.sub.2 is halogen, cyano, alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl,
--O-alkyl, --O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy,
--S-alkyl, alkylene-O-alkyl, alkylene-CO.sub.2H,
alkylene-CO.sub.2alkyl, alkylSO.sub.2, alkylSO.sub.2, alkylSO,
aralkylSO.sub.2, aralkylSO, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl; R.sub.3 is
halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroalkyl, --O-alkyl, --O-aryl,
--O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylenesulfonyl, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl; a is 0, 1, 2,
or 3; b is 1, 2 or 3; ##STR00167## are each independently phenyl or
pyridyl; R.sub.4 is hydrogen, cyano, alkyl, aryl, heteroaryl,
alkylene-OH, alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H; R.sub.5 and R.sub.6 are each
independently selected from the group consisting of hydrogen,
alkyl, alkylene-OH, aryl, alkylene-O-alkyl, --CO.sub.2H,
CO.sub.2-alkyl, alkylene-OC(O)alkyl, cycloalkyl, heterocyclo,
--C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl, --C(O)--Oalkyl,
--C(O)--Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or R.sub.5and R.sub.6, together
with the nitrogen to which they are attached, may form a 3, 4, 5,
or 6-membered saturated or unsaturated ring, optionally containing
1 or 2 additional heteroatoms selected from O, S, NH, or N-alkyl,
and optionally substituted on carbon with halogen, alkyl, hydroxyl,
or alkoxy; R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O -aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, --OPO.sub.2(S)NR.sub.p1R.sub.p2,
and --C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein Z' is hydroxyl or halogen; Z'' is H or halogen; R.sub.p1
and R.sub.p2 at each occurrence are independently hydrogen,
C.sub.1-C.sub.6-alkyl, or aryl; X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, --O--, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein R.sub.x1 and R.sub.x2
at each occurrence are independently selected from the group
consisting of hydrogen, hydroxyl, halogen, alkyl, --O-alkyl,
alkylyele-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and CO.sub.2-alkyl,
any of which may be optionally substituted on carbon with halogen;
or taken together R.sub.x1 and R.sub.x2 may form a 3, 4, 5, or 6
membered ring optionally containing 1 or 2 heteroatoms selected
from O, S, NH, or N-alkyl, which may itself be substituted on
carbon with halogen, hydroxyl, or alkyl; R.sub.x3 at each
occurrence is selected from the group consisting of hydrogen and
alkyl; n is an integer from 0 to 4; Y is selected from the group
consisting of heterocyclo or heteroaryl --CR.sub.y1R.sub.y2,
--CR.sub.y1R.sub.y2--NR.sub.y3--, --NR.sub.y3(CO)--, --(CO)--,
--O--, --S--, --SO--, --SO.sub.2--, --CR.sub.y1R.sub.y2--S--,
--CR.sub.y1R.sub.y2--O--, --COO--, and --NR.sub.y3SO.sub.2--;
wherein R.sub.y1, R.sub.y2, R.sub.y3 at each occurrence are
hydrogen or alkyl which may be substituted on carbon with halogen,
hydroxyl, or alkyl; or R.sub.y3 or --CR.sub.y1R.sub.y2 and one of
R.sub.5 or R.sub.6, together with the nitrogens to which they are
attached, form a 5, 6, or 7-membered ring, optionally substituted
on carbon with halogen, hydroxyl, or alkyl; and R.sub.8a and
R.sub.8b are each independently hydrogen, halogen, alkyl, or taken
together with the carbon to which they are attached, may form a 3,
4, 5, or 6-membered ring, optionally containing 1 or 2 heteroatoms
selected from NH, N-alkyl, O, or S, and optionally substituted on
carbon with halogen, or alkyl.
2. The compound of claim 1, wherein R.sub.1 is benzyloxy.
3. The compound of claim 1, wherein Y is selected from the group
consisting of ##STR00168##
4. The compound of claim 1, wherein Y is selected from the group
consisting of CH.sub.2, CH.sub.2NH, Y is NH(CO), Y is NMe(CO) and
C.dbd.O.
5. A compound of formula II ##STR00169## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1a is aryl or heteroaryl,
either of which may be optionally substituted on carbon with 1, 2,
or 3 groups selected from halo, alkyl, hydroxyl, or --O-alkyl;
R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl, --O-aryl,
--O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl; R.sub.3 is halogen, cyano, alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl,
--O-alkyl, --O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy,
--S-alkyl, alkylene-O-alkyl, alkylene-CO.sub.2H,
alkylene-CO.sub.2alkyl, alkylSO.sub.2, alkylenesulfonyl,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl; a is 0, 1, 2, or 3; b is 1, 2 or 3;
##STR00170## are each independently phenyl or pyridyl; R.sub.4 is
hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-OH, aryl,
alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H; R.sub.5and R.sub.6 are each
independently selected from the group consisting of hydrogen,
alkyl, alkylene-OH, aryl, alkylene-O-alkyl, --CO.sub.2H,
CO.sub.2-alkyl, alkylene-OC(O)alkyl, cycloalkyl, heterocyclo,
--C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl, --C(O)--Oalkyl,
--C(O)--Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or R.sub.5 and R.sub.6,
together with the nitrogen to which they are attached, may form a
3, 4, 5, or 6-membered saturated or unsaturated ring, optionally
containing 1 or 2 additional heteroatoms selected from O, S, NH, or
N-alkyl, and optionally substituted on carbon with halogen, alkyl,
hydroxyl, or alkoxy; R.sub.7 is selected from the group consisting
of alkyl, --OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl,
--C(O)O-aryl, --CH.sub.2.dbd.CHCO.sub.2H,
--CH.sub.2.dbd.CHC(O)O-alkyl, --CH.sub.2.dbd.CHC(O)O-aryl,
--OPO.sub.2R.sub.p1R.sub.p2, --OPO.sub.3R.sub.p1R.sub.p2,
--CH.sub.2PO.sub.3R.sub.p1R.sub.p2, --OPO.sub.2(S)R.sub.p1R.sub.p2,
--OPO.sub.2(S)NR.sub.p1R.sub.p2, and
--C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein Z' is hydroxyl or halogen; Z'' is H or halogen; R.sub.p1
and R.sub.p2 at each occurrence are independently hydrogen,
C.sub.1-C.sub.6-alkyl, or aryl; X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, --O--, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein R.sub.x1 and R.sub.x2
at each occurrence are independently selected from the group
consisting of hydrogen, hydroxyl, halogen, alkyl, --O-alkyl,
alkylyene-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and CO.sub.2-alkyl,
any of which may be optionally substituted on carbon with halogen;
or taken together R.sub.x1 and R.sub.x2 may form a 3, 4, 5, or 6
membered ring optionally containing 1 or 2 heteroatoms selected
from O, S, NH, or N-alkyl, which may itself be substituted on
carbon with halogen, hydroxyl, or alkyl; R.sub.x3 at each
occurrence is selected from the group consisting of hydrogen and
alkyl; n is an integer from 0 to 4; and ##STR00171## is a
heteroaryl ring containing up to four heteroatoms selected from N,
O, or S, optionally substituted on carbon with halogen or alkyl,
wherein Y.sub.1 is N, S, or O; Y.sub.2 and Y.sub.3 are each
independently C, N, O, or S; provided that when ##STR00172##
contains an N--H, that hydrogen may be replaced with alkyl; Y.sub.4
is C or N; and R.sub.8a and R.sub.8b are each independently
hydrogen, halogen, alkyl, or taken together with the carbon to
which they are attached, may form a 3, 4, 5, or 6-membered ring,
optionally containing 1 or 2 heteroatoms selected from NH, N-alkyl,
O, or S, and optionally substituted on carbon with halogen, or
alkyl
6. A compound of formula III: ##STR00173## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1a is aryl or heteroaryl,
either of which may be optionally substituted on carbon with 1, 2,
or 3 groups selected from halo, alkyl, hydroxyl, or --O-alkyl;
R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl, --O-aryl,
--O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl; R.sub.3 is halogen, cyano, alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl,
--O-alkyl, --O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy,
--S-alkyl, alkylene-O-alkyl, alkylene-CO.sub.2H,
alkylene-CO.sub.2alkyl, alkylSO.sub.2, alkylenesulfonyl,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl; a is 0, 1, 2, or 3; b is 1, 2, or 3;
##STR00174## are each independently phenyl or pyridyl; R.sub.4 is
hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-OH, aryl,
alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H; R.sub.5 and R.sub.6 are each
independently selected from the group consisting of hydrogen,
alkyl, alkylene-OH, aryl, alkylene-O-alkyl, --CO.sub.2H,
CO.sub.2-alkyl, alkylene-OC(O)alkyl, cycloalkyl, heterocyclo,
--C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl, --C(O)--Oalkyl,
--C(O)--Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or R.sub.5and R.sub.6, together
with the nitrogen to which they are attached, may form a 3, 4, 5,
or 6-membered saturated or unsaturated ring, optionally containing
1 or 2 additional heteroatoms selected from O, S, NH, or N-alkyl,
and optionally substituted on carbon with halogen, alkyl, hydroxyl,
or alkoxy; R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, --OPO.sub.2(S)NR.sub.p1R.sub.p2,
and --C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein Z' is hydroxyl or halogen; Z'' is H or halogen; R.sub.p1
and R.sub.p2 at each occurrence are independently hydrogen,
C.sub.1-C.sub.6-alkyl, or aryl; X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, --O--, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein R.sub.x1 and R.sub.x2
at each occurrence are independently selected from the group
consisting of hydrogen, hydroxyl, halogen, alkyl, --O-alkyl,
alkylyene-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and CO.sub.2-alkyl,
any of which may be optionally substituted on carbon with halogen;
or taken together R.sub.x1 and R.sub.x2 may form a 3, 4, 5, or 6
membered ring optionally containing 1 or 2 heteroatoms selected
from O, S, NH, or N-alkyl, which may itself be substituted on
carbon with halogen, hydroxyl, or alkyl; R.sub.x3 at each
occurrence is selected from the group consisting of hydrogen and
alkyl; n is an integer from 0 to 4; and Y is --CH.sub.2NR'''--,
--CH.sub.2NR'''(CO)--, --CHFNR'''--, --CHFNR'''(CO)--,
--CF.sub.2NR'''--, --CF.sub.2NR'''(CO)--, --CH.sub.2(CO)--,
--CHF(CO)--, --CF.sub.2(CO)--, --(CO)CF.sub.2--,
--CH.sub.2(CHOH)--, --CHF(CHOH)--, --CF.sub.2(CHOH)--,
--(CHOH)CF.sub.2--, --NH(CO)--, --(CO)--, --(CO).sub.2--, --O--,
--S--, --SO--, --SO.sub.2--, --CH.sub.2O--, --CH.sub.2CH.sub.2O--,
--CH.sub.2OCH.sub.2--, --OCH.sub.2O--, --CH.sub.2S--,
--CH.sub.2SO--, --CH.sub.2SO.sub.2--, --CHFO--, --CHFS--,
--CHFSO--, --CHFSO.sub.2--, --CF.sub.2O----CF.sub.2S--,
--CF.sub.2SO--, --CF.sub.2SO.sub.2--, --NR'''SO.sub.2--,
--CF.sub.2--, --CF.sub.2CF.sub.2--, --CF.sub.2CF.sub.2CF.sub.2--,
wherein R''' is H or alkyl; and R.sub.8a and R.sub.8b are each
independently hydrogen, halogen, alkyl, or taken together with the
carbon to which they are attached, may form a 3, 4, 5, or
6-membered ring, optionally containing 1 or 2 heteroatoms selected
from NH, N-alkyl, O, or S, and optionally substituted on carbon
with halogen, or alkyl.
7. The compound of claim 1, wherein R.sub.4 is selected from the
group consisting of hydrogen, methyl and hydroxymethyl.
8. The compound of claim 1, wherein R.sub.5and R.sub.6 are each
independently hydrogen.
9. The compound of claim 1, wherein R.sub.7 is selected from the
group consisting of OH, CO.sub.2H, CO.sub.2Me, CO.sub.2Et,
CO.sub.2-phenyl and --OP(O).sub.3H.sub.2.
10. The compound of claim 1, wherein X is selected from the group
consisting of CH2, NH, N-alkyl, O, S, SO, SO.sub.2 and CO.
11. The compound of claim 1, wherein, R.sub.8a and R.sub.8b are
each independently hydrogen.
12. A compound selected from the group consisting of: ##STR00175##
##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180##
##STR00181## wherein n is 0, 1, or 2 for the above compounds, and
pharmaceutically acceptable salts, phosphate derivatives, phosphate
mimics, or phosphate precursor analogs thereof.
13. The compound as defined in claim 1 or a pharmaceutically
acceptable salt, phosphate derivative, phosphate mimic, or
phosphate precursor analog thereof for use as a therapeutic
substance.
14. The compound as defined in claim 1 or a pharmaceutically
acceptable salt, phosphate derivative, phosphate mimic, or
phosphate precursor analog thereof for use in the treatment of a
sphingosine associated disorder.
15. The compound as defined in claim 1 or a pharmaceutically
acceptable salt, phosphate derivative, phosphate mimic, or
phosphate precursor analog thereof for use in the treatment of
multiple sclerosis.
16. (canceled)
17. (canceled)
18. A method of treating a sphingosine 1-phosphate associated
disorder comprising administering to a subject a therapeutically
effective amount of a compound as defined in claim 1 or a
pharmaceutically acceptable salt, phosphate derivative, phosphate
mimic, or a phosphate precursor analog thereof.
19. A pharmaceutical composition comprising a compound as defined
in claim 1 or a pharmaceutically acceptable salt, phosphate
derivative, phosphate mimic, or a phosphate precursor analog
thereof.
20. A process for the preparation of a pharmaceutical composition
according to claim 19.
21. A process for the preparation of a compound as defined in claim
1 or a pharmaceutically acceptable salt, phosphate derivative,
phosphate mimic, or phosphate precursor analog thereof.
Description
RELATED APPLICATIONS
[0001] This application is related and claims priority to U.S.
provisional application Ser. No. 60/821,425, filed Aug. 4, 2006;
U.S. provisional application Ser. No. 60/827,928, filed Oct. 3,
2006; U.S. provisional application Ser. No. 60/821,432, filed Aug.
4, 2006; and U.S. provisional application Ser. No. 60/827,941,
filed Oct. 3, 2006. The entire contents of each of the foregoing
applications are incorporated herein by this reference.
BACKGROUND OF THE INVENTION
[0002] Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid
metabolite that is secreted by hematopoietic cells and stored and
released from activated platelets. S1P is produced by the
sphingosine kinase-catalyzed phosphorylation of sphingosine. S1P
receptors (S1P-1, -2, -3, -4, and -5) are activated via binding
S1P. The receptors are involved in a variety of cellular processes,
including cell proliferation and differentiation, cell survival,
cell invasion, lymphocyte trafficking, and cell migration.
[0003] Administration of S1P to an animal results in sequestration
of lymphocytes into the lymph nodes and Peyers patches without
causing lymphocyte depletion. This activity, which is of potential
utility in treating diseases or conditions associated with
inappropriate immune response, such as organ transplant rejection,
autoimmune diseases such as multiple sclerosis and rheumatoid
arthritis, as well as other disorders modulated by lymphocyte
trafficking such as diabetes, hepatitis C (HCV) and cancer, is
believed to proceed via activation of the S1P-1 receptor.
Administration of S1P in vivo has been shown to cause hypotension
and bradycardia, which are believed to be due to signaling through
one or more of the other S1P receptors, i.e. S1P-2 to S1P-5.
Accordingly, there is a need for compounds which are potent and
selective agonists of the S1P-1 receptor.
SUMMARY OF THE INVENTION
[0004] These and other needs are met by the present invention which
is directed, at least in part, to a compound of formula I
##STR00001##
[0005] or a pharmaceutically acceptable salt thereof, wherein:
[0006] R.sub.1 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, --O-alkyl,
--O-aryl, --O-heteroaryl, --S-alkyl, alkylene-O-alkyl,
alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl, alkylSO.sub.2, alkylSO,
aralkylSO.sub.2, aralkylSO, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl --CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, or dialkylamino, any of which
may be optionally substituted on carbon with 1, 2, or 3 groups
selected from halo, alkyl, OH, or --O-alkyl;
[0007] R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl;
[0008] R.sub.3 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylenesulfonyl, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl --CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl;
[0009] a is 0, 1, 2, or 3;
[0010] b is 1, 2 or 3;
##STR00002##
[0011] are each independently phenyl or pyridyl;
[0012] R.sup.4 is hydrogen, cyano, alkyl, aryl, heteroaryl,
alkylene-OH, alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H;
[0013] R.sub.5 and R.sub.6 are each independently selected from the
group consisting of hydrogen, alkyl, alkylene-OH, aryl,
alkylene-O-alkyl, --CO.sub.2H, CO.sub.2-alkyl, alkylene-OC(O)alkyl,
cycloalkyl, heterocyclo, --C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl,
--C(O)--Oalkyl, --C(O)-Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or
[0014] R.sub.5 and R.sub.6, together with the nitrogen to which
they are attached, may form a 3, 4, 5, or 6-membered saturated or
unsaturated ring, optionally containing 1 or 2 additional
heteroatoms selected from O, S, NH, or N-alkyl, and optionally
substituted on carbon with halogen, alkyl, hydroxyl, or alkoxy;
[0015] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, --OPO.sub.2(S)NR.sub.p1R.sub.p2,
and --C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein
[0016] Z' is hydroxyl or halogen;
[0017] Z'' is H or halogen;
[0018] R.sub.p1 and R.sub.p2 at each occurrence are independently
hydrogen, C.sub.1-C.sub.6-alkyl, or aryl;
[0019] X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, --O--, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--, wherein
[0020] R.sub.x1 and R.sub.x2 at each occurrence are independently
selected from the group consisting of hydrogen, hydroxyl, halogen,
alkyl, --O-alkyl, alkylyele-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and
CO.sub.2-alkyl, any of which may be optionally substituted on
carbon with halogen; or taken together R.sub.x1 and R.sub.x2 may
form a 3, 4, 5, or 6 membered ring optionally containing 1 or 2
heteroatoms selected from O, S, NH, or N-alkyl, which may itself be
substituted on carbon with halogen, hydroxyl, or alkyl;
[0021] R.sub.x3 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0022] n is an integer from 0 to 4;
[0023] Y is selected from the group consisting of heterocyclo or
heteroaryl --CR.sub.y1R.sub.y2, --CR.sub.y1R.sub.y2--NR.sub.y3--,
--NR.sub.y3(CO)--, --(CO)--, --O--, --S--, --SO--, --SO.sub.2--,
--CR.sub.y1R.sub.y2--S--, --CR.sub.y1R.sub.y2--O--, --COO--, and
--NR.sub.y3SO.sub.2--; wherein
[0024] R.sub.y1, R.sub.y2, R.sub.y3 at each occurrence are hydrogen
or alkyl which may be substituted on carbon with halogen, hydroxyl,
or alkyl; or
[0025] R.sub.y3 or --CR.sub.y1R.sub.y2 and one of R.sub.5 or
R.sub.6, together with the nitrogens to which they are attached,
form a 5, 6, or 7-membered ring, optionally substituted on carbon
with halogen, hydroxyl, or alkyl; and
[0026] R.sub.8a and R.sub.8b are each independently hydrogen,
halogen, alkyl, or taken together with the carbon to which they are
attached, may form a 3, 4, 5, or 6-membered ring, optionally
containing 1 or 2 heteroatoms selected from NH, N-alkyl, O, or S,
and optionally substituted on carbon with halogen, or alkyl.
[0027] The present invention also provides a compound of formula
II
##STR00003##
[0028] or a pharmaceutically acceptable salt thereof, wherein:
[0029] R.sub.1a is aryl or heteroaryl, either of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halo, alkyl, hydroxyl, or --O-alkyl;
[0030] R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl;
[0031] R.sub.3 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylenesulfonyl, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl;
[0032] a is 0, 1, 2, or 3;
[0033] b is 1, 2 or 3;
##STR00004##
[0034] are each independently phenyl or pyridyl;
[0035] R.sub.4 is hydrogen, cyano, alkyl, aryl, heteroaryl,
alkylene-OH, aryl, alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H;
[0036] R.sub.5 and R.sub.6 are each independently selected from the
group consisting of hydrogen, alkyl, alkylene-OH, aryl,
alkylene-O-alkyl, --CO.sub.2H, CO.sub.2-alkyl, alkylene-OC(O)alkyl,
cycloalkyl, heterocyclo, --C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl,
--C(O)--Oalkyl, --C(O)-Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or
[0037] R.sub.5 and R.sub.6, together with the nitrogen to which
they are attached, may form a 3, 4, 5, or 6-membered saturated or
unsaturated ring, optionally containing 1 or 2 additional
heteroatoms selected from O, S, NH, or N-alkyl, and optionally
substituted on carbon with halogen, alkyl, hydroxyl, or alkoxy;
[0038] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl,
--C(O)O-aryl, --CH.sub.2.dbd.CHCO.sub.2H,
--CH.sub.2.dbd.CHC(O)O-alkyl, --CH.sub.2.dbd.CHC(O)O-aryl,
--OPO.sub.2R.sub.p1R.sub.p2,
[0039] --OPO.sub.3R.sub.p1R.sub.p2,
--CH.sub.2PO.sub.3R.sub.p1R.sub.p2, --OPO.sub.2(S)R.sub.p1R.sub.p2,
--OPO.sub.2(S)NR.sub.p1R.sub.p2, and
--C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein
[0040] Z' is hydroxyl or halogen;
[0041] Z'' is H or halogen;
[0042] R.sub.p1 and R.sub.p2 at each occurrence are independently
hydrogen, C.sub.1-C.sub.6-alkyl, or aryl;
[0043] X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, --O--, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x1).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein
[0044] R.sub.x1 and R.sub.x2 at each occurrence are independently
selected from the group consisting of hydrogen, hydroxyl, halogen,
alkyl, --O-alkyl, alkylyene-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and
CO.sub.2-alkyl, any of which may be optionally substituted on
carbon with halogen; or taken together R.sub.x1 and R.sub.x2 may
form a 3, 4, 5, or 6 membered ring optionally containing 1 or 2
heteroatoms selected from O, S, NH, or N-alkyl, which may itself be
substituted on carbon with halogen, hydroxyl, or alkyl;
[0045] R.sub.x3 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0046] n is an integer from 0 to 4; and
##STR00005##
[0047] is a heteroaryl ring containing up to four heteroatoms
selected from N, O, or S, optionally substituted on carbon with
halogen or alkyl, wherein
[0048] Y.sub.1 is N, S, or O;
[0049] Y.sub.2 and Y.sub.3 are each independently C, N, O, or S;
provided that when
##STR00006##
contains an N--H, that hydrogen may be replaced with alkyl;
[0050] Y.sub.4 is C or N; and
[0051] R.sub.8a and R.sub.8b are each independently hydrogen,
halogen, alkyl, or taken together with the carbon to which they are
attached, may form a 3, 4, 5, or 6-membered ring, optionally
containing 1 or 2 heteroatoms selected from NH, N-alkyl, O, or S,
and optionally substituted on carbon with halogen, or alkyl
[0052] The present invention also provides a compound of formula
III
##STR00007##
[0053] or a pharmaceutically acceptable salt thereof, wherein:
[0054] R.sub.1a is aryl or heteroaryl, either of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halo, alkyl, hydroxyl, or --O-alkyl;
[0055] R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl;
[0056] R.sub.3 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylenesulfonyl, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl;
[0057] a is 0, 1, 2, or 3;
[0058] b is 1, 2, or 3;
##STR00008##
[0059] are each independently phenyl or pyridyl;
[0060] R.sub.4 is hydrogen, cyano, alkyl, aryl, heteroaryl,
alkylene-OH, aryl, alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H;
[0061] R.sub.5 and R.sub.6 are each independently selected from the
group consisting of hydrogen, alkyl, alkylene-OH, aryl,
alkylene-O-alkyl, --CO.sub.2H, CO.sub.2-alkyl, alkylene-OC(O)alkyl,
cycloalkyl, heterocyclo, --C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl,
--C(O)--Oalkyl, --C(O)--Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or
[0062] R.sub.5 and R.sub.6, together with the nitrogen to which
they are attached, may form a 3, 4, 5, or 6-membered saturated or
unsaturated ring, optionally containing 1 or 2 additional
heteroatoms selected from O, S, NH, or N-alkyl, and optionally
substituted on carbon with halogen, alkyl, hydroxyl, or alkoxy;
[0063] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, --OPO.sub.2(S)NR.sub.p1R.sub.p2,
and --C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein
[0064] Z' is hydroxyl or halogen;
[0065] Z'' is H or halogen;
[0066] R.sub.p1 and R.sub.p2 at each occurrence are independently
hydrogen, C.sub.1-C.sub.6-alkyl, or aryl;
[0067] X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, --O--, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein
[0068] R.sub.x1 and R.sub.x2 at each occurrence are independently
selected from the group consisting of hydrogen, hydroxyl, halogen,
alkyl, --O-alkyl, alkylyene-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and
CO.sub.2-alkyl, any of which may be optionally substituted on
carbon with halogen; or taken together R.sub.x1 and R.sub.x2 may
form a 3, 4, 5, or 6 membered ring optionally containing 1 or 2
heteroatoms selected from O, S, NH, or N-alkyl, which may itself be
substituted on carbon with halogen, hydroxyl, or alkyl;
[0069] R.sub.x3 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0070] n is an integer from 0 to 4; and
[0071] Y is --CH.sub.2NR'''--, --CH.sub.2NR'''(CO--, --CHFNR'''--,
--CHFNR'''(CO)--, --CF.sub.2NR'''--, --CF.sub.2NR'''(CO)--,
--CH.sub.2(CO)--, --CHF(CO)--, --CF.sub.2(CO)--, --(CO)CF.sub.2--,
--CH.sub.2(CHOH)--, --CHF(CHOH)--, --CF.sub.2(CHOH)--,
--(CHOH)CF.sub.2--, --NH(CO)--, --(CO)--, --(CO).sub.2--, --O--,
--S--, --SO--, --SO.sub.2--, --CH.sub.2O--, --CH.sub.2CH.sub.2O--,
--CH.sub.2OCH.sub.2--, --OCH.sub.2O--, --CH.sub.2S--,
--CH.sub.2SO--, --CH.sub.2SO.sub.2--, --CHFO--, --CHFS--,
--CHFSO--, --CHFSO.sub.2--, --CF.sub.2O--, --CF.sub.2S--,
--CF.sub.2SO--, --CF.sub.2SO.sub.2--, --NR'''SO.sub.2--,
--CF.sub.2--, --CF.sub.2CF.sub.2--, --CF.sub.2CF.sub.2CF.sub.2--,
wherein R''' is H or alkyl; and
[0072] R.sub.8a and R.sub.8b are each independently hydrogen,
halogen, alkyl, or taken together with the carbon to which they are
attached, may form a 3, 4, 5, or 6-membered ring, optionally
containing 1 or 2 heteroatoms selected from NH, N-alkyl, O, or S,
and optionally substituted on carbon with halogen, or alkyl.
[0073] The present invention is also directed to a compound which
is:
##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##
##STR00014## ##STR00015##
wherein n is 0, 1, or 2 for the above compounds, as well as
pharmaceutically acceptable salts, phosphate derivatives, phosphate
mimics, or phosphate precursor analogs thereof.
[0074] The invention is also directed to a method of treating an
autoimmune disorder, comprising administering to a subject in need
thereof a pharmaceutically acceptable amount of any of the
compounds described herein, e.g., compounds of formulae I-III.
[0075] The invention is also directed to a method treating
transplant rejection comprising administering to a subject in need
thereof a pharmaceutically acceptable amount of any of the
compounds described herein, e.g., compounds of formulae I-III.
[0076] The invention is also directed to a method treating multiple
sclerosis comprising administering to a subject in need thereof a
pharmaceutically acceptable amount of any of the compounds
described herein, e.g., compounds of formulae I-III.
[0077] The invention is also directed to a method treating asthma
comprising administering to a subject in need thereof a
pharmaceutically acceptable amount of any of the compounds
described herein, e.g., compounds of formulae I-III.
[0078] The invention is also directed to a method treating
rheumatoid arthritis comprising administering to a subject in heed
thereof a pharmaceutically acceptable amount of any of the
compounds described herein, e.g., compounds of formulae I-III.
[0079] The invention is also directed to a method treating cancer
comprising, administering to a subject in need thereof a
pharmaceutically acceptable amount of any of the compounds
described herein, e.g., compounds of formulae I-III.
[0080] The invention is also directed to a method treating
hepatitis C (HCV) comprising, administering to a subject in need
thereof a pharmaceutically acceptable amount of any of the
compounds described herein, e.g., compounds of formulae I-III.
[0081] The invention is also directed to a method treating diabetes
comprising, administering to a subject in need thereof a
pharmaceutically acceptable amount of any of the compounds
described herein, e.g., compounds of formulae I-III.
[0082] The invention is also directed to a pharmaceutical
composition, comprising any of the compounds described herein,
e.g., compounds of formulae I-III and a pharmaceutically acceptable
carrier.
[0083] The invention is also directed to a process for making any
of the compounds described herein, e.g., compounds of formulae
I-III, e.g., a method as provided in Schemes 1, 2, 3 and 4.
BRIEF DESCRIPTION OF THE DRAWING
[0084] FIG. 1 is a graph showing the results of the lymphopenia
assay for certain compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0085] The following definitions are used, unless otherwise
described.
[0086] "Halogen" or "halo" means fluoro (F), chloro (Cl), bromo
(Br), or iodo (I).
[0087] The term "hydrocarbon" used alone or as a suffix or prefix,
refers to any structure comprising only carbon and hydrogen atoms
up to 14 carbon atoms.
[0088] The term "hydrocarbon radical" or "hydrocarbyl" used alone
or as a suffix or prefix, refers to any structure as a result of
removing one or more hydrogens from a hydrocarbon.
[0089] The term "alkyl" used alone or as a suffix or prefix, refers
to monovalent straight or branched chain hydrocarbon radicals
comprising 1 to about 12 carbon atoms.
[0090] The term "alkylene" used alone or as suffix or prefix,
refers to divalent straight or branched chain hydrocarbon radicals
comprising 1 to about 12 carbon atoms, which serves to links two
structures together.
[0091] The term "cycloalkyl" used alone or as suffix or prefix,
refers to a saturated or partially unsaturated monovalent
ring-containing hydrocarbon radical comprising at least 3 up to
about 12 carbon atoms.
[0092] The term "aryl" used alone or as suffix or prefix, refers to
a monovalent hydrocarbon radical having one or more polyunsaturated
carbon rings having aromatic character, and comprising 5 up to
about 14 carbon atoms.
[0093] The term "heterocycle" used alone or as a suffix or prefix,
refers to a ring-containing structure or molecule having one or
more multivalent heteroatoms, independently selected from N, O and
S, as a part of the ring structure and including at least 3 and up
to about 20 atoms in the ring(s). Heterocycle may be saturated or
unsaturated, containing one or more double bonds, and heterocycle
may contain more than one ring. When a heterocycle contains more
than one ring, the rings may be fused or unfused. Fused rings
generally refer to at least two rings share two atoms therebetween.
Heterocycle may have aromatic character or may not have aromatic
character.
[0094] The terms "heterocyclic group", "heterocyclic moiety",
"heterocyclic", or "heterocyclo" used alone or as a suffix or
prefix, refers to a radical derived from a heterocycle by removing
one or more hydrogens therefrom.
[0095] The term "heterocyclyl" used alone or as a suffix or prefix,
refers a monovalent radical derived from a heterocycle by removing
one hydrogen therefrom.
[0096] The term "heteroaryl" used alone or as a suffix or prefix,
refers to a heterocyclyl having aromatic character.
[0097] Heterocycle includes, for example, monocyclic heterocycles
such as: aziridine, oxirane, thiirane, azetidine, oxetane,
thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine,
pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran
tetrahydrofuran, thiophane, piperidine,
1,2,3,6-tetrahydro-pyridine, piperazine, morpholine,
thiomorpholine, pyran, thiopyran, 2,3-dihydropyran,
tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane,
dioxane, homopiperidine, 2,3,4,7-tetrahydro-1H-azepine
homopiperazine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and
hexamethylene oxide.
[0098] In addition, heterocycle includes aromatic heterocycles
(heteroaryl groups), for example, pyridine, pyrazine, pyrimidine,
pyridazine, thiophene, furan, furazan, pyrrole, imidazole,
thiazole, oxazole, pyrazole, isothiazole, isoxazole,
1,2,3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3-oxadiazole,
1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole,
1,3,4-triazole, 1,3,4-thiadiazole, and 1,3,4-oxadiazole.
[0099] Additionally, heterocycle encompass polycyclic heterocycles,
for example, indole, indoline, isoindoline, quinoline,
tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline,
1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran,
2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman,
isochroman, xanthene, phenoxathiin, thianthrene, indolizine,
isoindole, indazole, purine, phthalazine, naphthyridine,
quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine,
perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine,
1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole,
benzimidazole, benztriazole, thioxanthine, carbazole, carboline,
acridine, pyrolizidine, and quinolizidine.
[0100] In addition to the polycyclic heterocycles described above,
heterocycle includes
[0101] polycyclic heterocycles wherein the ring fusion between two
or more rings includes more than one bond common to both rings and
more than two atoms common to both rings. Examples of such bridged
heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and
7-oxabicyclo[2.2.1]heptane.
[0102] Heterocyclyl includes, for example, monocyclic
heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl,
azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl,
2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl,
thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl,
morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl,
2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl,
1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl,
2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl, 1,3-dioxepanyl,
4,7-dihydro-1,3-dioxepinyl, and hexamethylene oxidyl.
[0103] In addition, heterocyclyl includes aromatic heterocyclyls or
heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl,
thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,
1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
[0104] Additionally, heterocyclyl encompasses polycyclic
heterocyclyls (including both aromatic or non-aromatic), for
example, indolyl, indolinyl, isoindolinyl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl,
2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl,
isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl,
isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,
phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl,
benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl,
thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl,
and quinolizidinyl.
[0105] In addition to the polycyclic heterocyclyls described above,
heterocyclyl includes polycyclic heterocyclyls wherein the ring
fusion between two or more rings includes more than one bond common
to both rings and more than two atoms common to both rings.
Examples of such bridged heterocycles include quinuclidinyl,
diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
[0106] The term "six-membered" used as prefix refers to a group
having a ring that contains six ring atoms.
[0107] The term "five-membered" used as prefix refers to a group
having a ring that contains five ring atoms.
[0108] A five-membered heteroaryl ring is a heteroaryl with a ring
having five ring atoms wherein 1, 2 or 3 ring atoms are
independently selected from N, O and S. Exemplary five-membered
ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,
thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,
1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.
[0109] A six-membered ring heteroaryl is a heteroaryl with a ring
having six ring atoms wherein 1, 2 or 3 ring atoms are
independently selected from N, O and S. Exemplary six-membered ring
heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and
pyridazinyl.
[0110] The term "aralkyl" refers to an alkyl group substituted with
an aryl group.
[0111] The term "heteroaralkyl" refers to an alkyl group
substituted with an heteroaryl group.
[0112] Unless otherwise specified, the term "substituted", when
used as a prefix, refers to a structure, molecule or group, wherein
one or more hydrogens are replaced with one or more alkyl groups,
or one or more chemical groups containing one or more heteroatoms
selected from N, O, S, F, Cl, Br, I, and P. Exemplary chemical
groups containing one or more heteroatoms include heterocyclyl,
--NO.sub.2, --O-alkyl, halo, --CF.sub.3, --CO.sub.2H, --CO.sub.2R,
--NH.sub.2, --SH, --NHR, --NR.sub.2, --SR, --SO.sub.3H,
--SO.sub.2R, --S(O)R, --CN, --OH, --C(O)NR.sub.2, --NRC(O)R, oxo
(.dbd.O), imino (.dbd.NR), thio (.dbd.S), and oximino (.dbd.N--OR),
wherein each "R" is alkyl as defined above. For example,
substituted phenyl may refer to nitrophenyl, pyridylphenyl,
methoxyphenyl, chlorophenyl, aminophenyl, and so on, wherein the
nitro, pyridyl, methoxy, chloro, and amino groups may replace any
suitable hydrogen on the phenyl ring.
[0113] The term "alkoxy" used alone or as a suffix or prefix,
refers to radicals of the general --O-alkyl, Exemplary alkoxy
groups includes methoxy, ethoxy, propoxy, isopropoxy, butoxy,
t-butoxy, isobutoxy, cyclopropylnethoxy, allyloxy, and
propargyloxy.
[0114] The term "amine" or "amino" used alone or as a suffix or
prefix, refers --NH.sub.2.
[0115] The term "alkylamino" used alone or as a suffix or prefix,
refers --NH(alkyl).
[0116] The term "dialkylamino" used alone or as a suffix or prefix,
refers --N(alkyl).sub.2.
[0117] "Acyl" used alone, as a prefix or suffix, means --C(O)--R,
wherein R hydrogen, hydroxyl, amino, alkylamino, dialkylamino, or
alkoxy, any of which may be substituted as provided by the
definition of "substituted" given above. Acyl groups include, for
example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy,
and dimethylcarbamoyl.
[0118] Some of the compounds in the present invention may exist as
stereoisomers, including enantiomers, diastereomers, and geometric
isomers. All of these forms, including (R), (S), epimers,
diastereomers, cis, trans, syn, anti, solvates (including
hydrates), tautomers, and mixtures thereof, are contemplated in the
compounds of the present invention.
[0119] The invention also relates to salts of the compounds of the
invention and, in particular, to pharmaceutically acceptable salts.
A "pharmaceutically acceptable salt" is a salt that retains the
desired biological activity of the parent compound and does not
impart any undesired toxicological effects. The salts can be, for
example, salts with a suitable acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
the like; acetic acid, oxalic acid, tartaric acid, succinic acid,
malic acid, benzoic acid, pamoic acid, alginic acid,
methanesulfonic acid, naphthalenesulfonic acid, and the like. Also
included are salts of cations such as ammonium, sodium, potassium,
lithium, zinc, copper, barium, bismuth, calcium, and the like; or
organic cations such as tetralkylammonium and trialkylammonium
cations. Combinations of the above salts are also useful. Salts of
other acids and/or cations are also included, such as salts with
trifluoroacetic acid, chloroacetic acid, and trichloroacetic acid.
The invention also includes different crystal forms, hydrates, and
solvates of the compounds of the invention.
[0120] The terms "phosphate precursor" and "phosphate precursor
analog," as used herein, refer to substituent moieties in invention
compounds that may be directly phosphorylated in vivo, or which may
be cleaved in vivo to reveal a moiety that may then be
phosphorylated in vivo. In certain embodiments, the phosphate
precursor may be L.sub.1-O--H or L.sub.1-O-L.sub.2, wherein L.sub.1
is a linking moiety and L.sub.2 is a labile moiety. Exemplary
embodiments of the phosphate precursor, include but are not limited
to -alkyl-OH, -halo-alkyl-OH, alkoxy-OH, -alkyl-OCOR.sup.a,
-halo-alkyl-OCOR.sup.a, -alkoxy-OCOR.sup.a,
-alkyl-OC(O)NR.sup.aR.sup.b, -halo-alkyl-OC(O)NHR.sup.aR.sup.b,
-alkoxy-OC(O)NR.sup.aR.sup.b, --(CH.sub.2).sub.qCO.sub.2R.sup.c,
and --(CH.sub.2).sub.nCH.sub.2.dbd.CHC(O)OR.sup.c, wherein
[0121] q is an integer between 0 and 4;
[0122] R.sup.a and R.sup.b are independently selected from the
group consisting of hydrogen, straight chain or branched
C.sub.1-C.sub.6-alkyl, all of which may be optionally substituted
with OH, halogen, straight chain or branched
C.sub.1-C.sub.6-alkoxy, straight chain or branched
halo-C.sub.1-C.sub.6-alkyl, straight chain or branched
halo-C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl,
hydroxyl-C.sub.1-C.sub.6-alkyl, carboxy-C.sub.1-C.sub.6-alkyl,
substituted or unsubstituted C.sub.3-C.sub.10 carbocyclic rings,
and substituted or unsubstituted C.sub.3-C.sub.10 heterocyclic
rings, which may contain one or more heteroatoms and may be
saturated or unsaturated; and
[0123] R.sup.c is selected from the group consisting of hydrogen,
straight chain or branched C.sub.1-C.sub.6-alkyl, straight chain or
branched halo-C.sub.1-C.sub.6-alkyl, substituted or unsubstituted
aryl group, and a prodrug derivatizing moiety (PDM).
[0124] The "linking moiety," may contain 1-8 atoms or may be a
bond, and serves as the connection point through which the
phosphate mimic, phosphate derivative, or phosphate precursor
substituent moieties are linked to the remaining structure of the
compounds of the invention. In certain embodiments, the linking
moiety may include, but is not limited to, substituted or
unsubstituted alkyl (e.g., methylene chains), substituted or
unsubstituted alkenyl (e.g., n-alkenes), substituted or
unsubstituted alkynyl, substituted or unsubstituted halo-alkyl,
substituted or unsubstituted alkoxy, and substituted or
unsubstituted halo-alkoxy. In specific embodiments, the linking
moiety may be carbonyl derivatized.
[0125] The language "labile moiety" refers to a moiety that is
subject to cleavage, for instance, by hydrolysis or enzymatic
degradation. In certain embodiments, the labile moiety is an ester
moiety, which may result in a carboxylate or hydroxyl derivative,
depending on the orientation of the ester functionality in the
molecule prior to cleavage.
[0126] The term "prodrug derivatizing moiety (PDM)" refers to a
moiety that derivatizes the compounds of the invention, resulting
in a prodrug. Such prodrugs are art-recognized, and are often used
to mask particular functionalities that are excessively reactive in
vivo. In certain embodiments the PDM is selected from the group
consisting of:
##STR00016##
[0127] The term "phosphate derivative" refers to substituent
moieties in invention compounds that contain a phosphate or
phosphate ester group. When a compound of the invention containing
a phosphate derivative is administered to a subject, the compound
may act as is in vivo or the phosphate derivative (within the
compound) may be cleaved and then re-phosphorylated in vivo leading
to an active compound. In certain embodiments, the phosphate
derivative may be selected from the group consisting of
--(CH.sub.2).sub.qOPO.sub.2R.sup.dR.sup.e,
--(CH.sub.2).sub.qOPO.sub.3R.sup.dR.sup.e, and
--(CH.sub.2).sub.qOPO.sub.2(S)R.sup.dR.sup.e, wherein
[0128] q is an integer between 0 and 4; and
[0129] R.sup.d and R.sup.e are each independently selected from the
group consisting of hydrogen, straight chain or branched
C.sub.1-C.sub.6-alkyl, straight chain or branched
halo-C.sub.1-C.sub.6-alkyl, substituted or unsubstituted aryl
group, and a prodrug derivatizing moiety (PDM).
[0130] The term "phosphate mimic" refers to substituent moieties in
invention compounds in which a phosphate substrate has been
replaced with a non-hydrolyzable functional group, resulting in a
moiety that mimics the structural and/or electronic attributes of a
phosphate or phosphate ester moiety. In certain embodiments, the
phosphate mimic is -L.sub.1-Z.sub.2, wherein L.sub.1 is a linking
moiety and Z.sub.2 is a non-hydrolyzable moiety covalently bonded,
to L.sub.1. In certain embodiments, the phosphate mimic is selected
from the group consisting of
--(CH.sub.2).sub.qCH.sub.2PO.sub.3R.sup.dR.sup.e, and
--(CH.sub.2).sub.qC(Y.sub.1)(Y.sub.2)PO.sub.3R.sup.dR.sup.e,
wherein
[0131] q is an integer between 0 and 4;
[0132] Y.sub.1 and Y.sub.2 are independently selected from the
group consisting of hydrogen, straight chain or branched
C.sub.1-C.sub.6-alkyl, all of which may be optionally substituted
with OH, halogen, straight chain or branched
C.sub.1-C.sub.6-alkoxy, straight chain or branched
halo-C.sub.1-C.sub.6-alkyl, straight chain or branched
halo-C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl,
hydroxyl-C.sub.1-C.sub.6-alkyl, carboxy-C.sub.1-C.sub.6-alkyl,
substituted or unsubstituted C.sub.3-C.sub.10 carbocyclic rings,
and substituted or unsubstituted C.sub.3-C.sub.10 heterocyclic
rings, which may contain one or more heteroatoms and may be
saturated or unsaturated; and
[0133] R.sup.d and R.sup.e are each independently selected from the
group consisting of hydrogen, straight chain or branched
C.sub.1-C.sub.6-alkyl, straight chain or branched
halo-C.sub.1-C.sub.6-alkyl, substituted or unsubstituted aryl
group, and a prodrug derivatizing moiety (PDM).
[0134] The language "non-hydrolyzable moiety" is art-recognized,
and refers to moieties containing bonds, such as carbon-phosphorous
bonds, that are not hydrolyzable in vivo.
Invention Compounds
[0135] In some aspects, the present invention is drawn to a
compound of formula I.
##STR00017##
[0136] or a pharmaceutically acceptable salt thereof, wherein:
[0137] R.sub.1 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, --O-alkyl,
--O-aryl, --O-heteroaryl, --S-alkyl, alkylene-O-alkyl,
alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl, alkylSO.sub.2, alkylSO,
aralkylSO.sub.2, aralkylSO, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, or dialkylamino, any of which
may be optionally substituted on carbon with 1, 2, or 3 groups
selected from halo, alkyl, OH, or --O-alkyl;
[0138] R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl;
[0139] R.sub.3 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylenesulfonyl, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl;
[0140] a is 0, 1, 2, or 3;
[0141] b is 1, 2 or 3;
##STR00018##
[0142] are each independently phenyl or pyridyl;
[0143] R.sub.4 is hydrogen, cyano, alkyl, aryl, heteroaryl,
alkylene-OH, alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H;
[0144] R.sub.5 and R.sub.6 are each independently selected from the
group consisting of hydrogen, alkyl, alkylene-OH, aryl,
alkylene-O-alkyl,--CO.sub.2H, CO.sub.2-alkyl, alkylene-OC(O)alkyl,
cycloalkyl, heterocyclo, --C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl,
--C(O)--Oalkyl, --C(O)--Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or
[0145] R.sub.5 and R.sub.6, together with the nitrogen to which
they are attached, may form a 3, 4, 5, or 6-membered saturated or
unsaturated ring, optionally containing 1 or 2 additional
heteroatoms selected from O, S, NH, or N-alkyl, and optionally
substituted on carbon with halogen, alkyl, hydroxyl, or alkoxy;
[0146] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, --OPO.sub.2(S)NR.sub.p1R.sub.p2,
and --C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein
[0147] Z' is hydroxyl or halogen;
[0148] Z'' is H or halogen;
[0149] R.sub.p1 and R.sub.p2 at each occurrence are independently
hydrogen, C.sub.1-C.sub.6-alkyl, or aryl;
[0150] X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, --O--, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein
[0151] R.sub.x1 and R.sub.x2 at each occurrence are independently
selected from the group consisting of hydrogen, hydroxyl, halogen,
alkyl, --O-alkyl, alkylyene-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and
CO.sub.2-alkyl, any of which may be optionally substituted on
carbon with halogen; or taken together R.sub.x1 and R.sub.x2 may
form a 3, 4, 5, or 6 membered ring optionally containing 1 or 2
heteroatoms selected from O, S, NH, or N-alkyl, which may itself be
substituted on carbon with halogen, hydroxyl, or alkyl;
[0152] R.sub.x3 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0153] n is an integer from 0 to 4;
[0154] Y is selected from the group consisting of heterocyclo or
heteroaryl-CR.sub.y1R.sub.y2, --CR.sub.y1R.sub.y2--NR.sub.y3--,
--NR.sub.y3(CO)--, --(CO)--, --O--, --S--, --SO--, --SO.sub.2--,
--CR.sub.y1R.sub.y2--S--, --CR.sub.y1R.sub.y2--O--, --COO--, and
--NR.sub.y3SO.sub.2--; wherein
[0155] R.sub.y1, R.sub.y2, R.sub.y3 at each occurrence are hydrogen
or alkyl which may be substituted on carbon with halogen, hydroxyl,
or alkyl; or
[0156] R.sub.y3 or --CR.sub.y1R.sub.y2 and one of R.sub.5 or
R.sub.6, together with the nitrogens to which they are attached,
form a 5, 6, or 7-membered ring, optionally substituted on carbon
with halogen, hydroxyl, or alkyl; and
[0157] R.sub.8a and R.sub.8b are each independently hydrogen,
halogen, alkyl, or taken together with the carbon to which they are
attached, may form a 3, 4, 5, or 6-membered ring, optionally
containing 1 or 2 heteroatoms selected from NH, N-alkyl, O, or S,
and optionally substituted on carbon with halogen, or alkyl.
[0158] It is to be understood that when the values for a and b are
less than the total number of open substituents on the ring, the
remainder of the substituents are hydrogen.
That is, if b is 1, the remaining three substituents on
##STR00019##
are hydrogen.
[0159] In some embodiments, R.sub.1 is benzyloxy.
[0160] The compounds of the present invention include a selectivity
enhancing moiety. The term "selectivity enhancing moiety (SEM)" is
defined in U.S. application Ser. No. 11/349069 filed on Feb. 6,
2006 which is assigned to the assignee of the present application,
the contents of which are incorporated herein by reference, refers
to one or more moieties that provide an enhancement in the
selectivity of the compound to which they are attached for the
S1P-1 receptor, as compared to the compound not containing the
moiety or moieties. The SEM confers selectivity to the compound to
which it is attached for the S1P-1 receptor as compared to, for
example, the S1P-2 to S1P-5 receptors. The enhancement conferred to
a compound by the SEM may be measured by, for example, determining
the binding specificity of a compound for the S1P-1 receptor and
one or more of the other S1P receptors. The enhancement conferred
to a compound by the SEM may be in the form of increased potency
for S1P-1 or decreased potency for any one of S1P-2 through S1P-5.
The SEM of the present application is defined in one embodiment as
for R.sub.2 and R.sub.3.
[0161] The SEM may be a halogen such as F or Cl. It may also be a
halo-substituted alkyl group such as CF.sub.3, CF.sub.2CF.sub.3,
CF.sub.2CF.sub.2CF.sub.3, CFHCF.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CF.sub.3, CHCl.sub.2, or CH.sub.2Cl. It may also be
cyano.
[0162] In certain embodiments, the SEM may possess a selectivity
enhancing orientation (SEO). The term "selectivity enhancing
orientation" or "SEO," is defined in U.S. application Ser. No.
11/349069 filed on Feb. 6, 2006 which is assigned to the assignee
of the present application, the contents of which are incorporated
herein by reference and as used herein refers to the relative
selectivity enhancement of a compound based on the orientation of
the SEM as well as the additional substituents on the ring, either
alone or in combination with each other. In particular, the SEO may
result from the orientation of the SEM on the ring to which it is
attached, in relation to any other ring and/or moiety attached to
the same ring. In one embodiment, the SEM on
##STR00020##
is in the ortho position relative to X in Formula I. In another
specific embodiment, the SEM is in the meta position relative to
X.
[0163] Thus, a specific value for R.sub.3 is trifluoromethyl.
Another specific value for R.sub.3 is fluoro. Another specific
value for R.sub.3 is chloro. Another specific value for R.sub.3 is
bromo, Another specific value for R.sub.3 is cyano. Another
specific value for R.sub.3 is methyl. Another specific value for
R.sub.3 is dimethylamino.
[0164] In some embodiments, a is 0. In other embodiments, a is
1.
[0165] In some embodiments, b is 1.
[0166] In some embodiments,
##STR00021##
In other embodiments,
##STR00022##
[0167] In some embodiments,
##STR00023##
In other embodiments,
##STR00024##
[0168] In some embodiments, R.sub.4 is hydrogen. In other
embodiments, R.sub.4 is methyl. In other embodiments, R.sub.4 is
hydroxymethyl.
[0169] In some embodiments, R.sub.5 and R.sub.6 are independently
hydrogen.
[0170] In some embodiments, R.sub.7 is OH. In other embodiments,
R.sub.7 is CO.sub.2H. In other embodiments, R.sub.7 is CO.sub.2Me
or CO.sub.2Et. Another In other embodiments, R.sub.7 is
CO.sub.2-phenyl. In other embodiments, R.sub.7 is
--OP(O).sub.3H.sub.2.
[0171] In some embodiments, X is CH.sub.2. In other embodiments, X
is NH or N-alkyl. In other embodiments, X is O. In other
embodiments, X is S, SO, or SO.sub.2. In other embodiments, X is
CO.
[0172] In some embodiments, Y is
##STR00025##
In other embodiments, Y is
##STR00026##
In other embodiments, Y is
##STR00027##
In other embodiments, Y is
##STR00028##
In other embodiments, Y is
##STR00029##
In some embodiments, Y is
##STR00030##
In other embodiments, Y is
##STR00031##
In other embodiments, Y is
##STR00032##
In other embodiments, Y is
##STR00033##
some embodiments, Y is
##STR00034##
In other embodiments, Y is
##STR00035##
In other embodiments, Y is
##STR00036##
In other embodiments, Y is
##STR00037##
Another specific value for Y is
##STR00038##
In some embodiments,
##STR00039##
In other embodiments, Y is
##STR00040##
In other embodiments, Y is
##STR00041##
In other embodiments, Y is
##STR00042##
In the above structures, R can be hydrogen or alkyl, and
##STR00043##
indicates a point of attachment.
[0173] In some embodiments, Y is CH.sub.2. In other embodiments, Y
is CH.sub.2NH. In other embodiments, Y is NH(CO). In other
embodiments, Y is NMe(CO). In other embodiments, Y is C.dbd.O.
[0174] In some embodiments,
##STR00044##
wherein
##STR00045##
indicate points of attachment. In some embodiments,
##STR00046##
[0175] As a note, it is to be understood that when Y is a two or
more atom unit that is not symmetric, then Y can be attached to
##STR00047##
in either orientation; that is, when Y is, for instance CH.sub.2NH,
it can be attached to
##STR00048##
to form
##STR00049##
and so on, wherein
##STR00050##
indicates the other point of attachment.
[0176] In some embodiments, R.sub.8a is hydrogen.
[0177] In some embodiments, R.sub.8b is hydrogen.
In some embodiments, compounds of the invention are compounds
wherein
[0178] R.sub.1 is absent, alkyl, aryl, heteroaryl, aralkoxy, or
heteroaralkoxy.
[0179] R.sub.4 is hydrogen, alkyl, or alkyl-OH;
[0180] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0181] R.sub.7 is selected from the group consisting of --OH,
alkyl-OH, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and
--C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2; wherein
[0182] X is CR.sub.x1R.sub.x2, NR.sub.x3, --O--, --S(O)--,
--S(O).sub.2--, --OS(O).sub.2--, --OS(O).sub.2O--, --C(O)--, or
--C(O)O--; wherein
[0183] R.sub.x3 is hydrogen or alkyl.
In other embodiments, compounds of the invention are compounds
wherein
[0184] R.sub.1 is absent, alkyl, or aryloxy;
[0185] R.sub.4 is hydrogen, alkyl, hydroxy-alkyl, aryl,
alkoxy-alkyl, or carboxy-alkyl;
[0186] R.sub.5 and R.sub.6 are each independently hydrogen, alkyl,
hydroxy-alkyl, aryl, alkoxy-alkyl, --C(O)-alkyl, C(O)-aryl,
--C(O)--Oalkyl, or C(O)--Oaryl,;
[0187] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O;
wherein
[0188] R.sub.p1R.sub.p2 are each independently hydrogen, alkyl, or
aryl; and
[0189] X is CR.sub.x1R.sub.x2, NR.sub.x3, --O--, --S--, --S(O)--,
--SC(O)--, or --C(O)--, wherein R.sub.x1, R.sub.x2, and R.sub.x3
are each independently hydrogen or alkyl.
In other embodiments, compounds of the invention are compounds
wherein
[0190] R.sub.1 is alkyl, aryl, heteroaryl, aralkoxy, or
heteroaralkoxy.
[0191] R.sub.4 is hydrogen, alkyl, or alkyl-OH;
[0192] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0193] R.sub.7 is selected from the group consisting of --OH,
alkyl-OH, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and
--C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2; wherein
[0194] X is CR.sub.x1R.sub.x2, NR.sub.x3, --O--, --S--, --S(O)--,
--S(O).sub.2--, --OS(O).sub.2--, --OS(O).sub.2O--, --C(O)--, or
--C(O)O--; wherein
[0195] R.sub.x3 is hydrogen or alkyl.
In still other embodiments, compounds of the invention are
compounds wherein
[0196] R.sub.1 is alkyl, or aryloxy;
[0197] R.sub.4 is hydrogen, alkyl, hydroxy-alkyl, aryl,
alkoxy-alkyl, or carboxy-alkyl;
[0198] R.sub.5 and R.sub.6 are each independently hydrogen, alkyl,
hydroxy-alkyl, aryl, alkoxy-alkyl, --C(O)-alkyl, C(O)-aryl,
--C(O)--Oalkyl, or C(O)--Oaryl;
[0199] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O;
wherein
[0200] R.sub.p1R.sub.p2are each independently hydrogen, alkyl, or
aryl; and
[0201] X is CR.sub.x1R.sub.x2, NR.sub.x3, --O--, --S--, --S(O)--,
--S(O).sub.2--, or --C(O)--, wherein R.sub.x1, R.sub.x2, and
R.sub.x3 are each independently hydrogen or alkyl.
In yet other embodiments, compounds of the invention are compounds
wherein
##STR00051##
[0202] R.sub.1 is aryloxy;
[0203] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0204] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0205] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
and
[0206] Y is
##STR00052##
In still other embodiments, compounds of the invention are
compounds wherein
##STR00053##
[0207] R.sub.1 is aryloxy;
[0208] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0209] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;.
[0210] R.sub.7 is OH, OP(O).sub.3H.sub.2, or CO.sub.2H;
[0211] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
and
[0212] Y is
##STR00054##
In further embodiments, compounds of the invention are compounds
wherein
##STR00055##
[0213] R.sub.1 is aryloxy;
[0214] R.sub.3 is CF.sub.3;
[0215] a is 0;
[0216] b is 1;
[0217] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0218] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0219] R.sub.7 is OH, OP(O).sub.3H.sub.2, or CO.sub.2H;
[0220] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
[0221] R.sub.8a and R.sub.8b are hydrogen; and
[0222] Y is
##STR00056##
In yet other embodiments, compounds of the invention are compounds
wherein
##STR00057##
[0223] R.sub.2 is aryloxy;
[0224] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0225] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0226] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
and
[0227] Y is CH.sub.2NH, NH(CO), or NMe(CO).
In still other embodiments, compounds of the invention are
compounds wherein
##STR00058##
[0228] R.sub.2 is aryloxy;
[0229] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0230] R.sub.6 is hydrogen or alkyl;
[0231] R.sub.7 is OH, OP(O).sub.3H.sub.2, or CO.sub.2H;
[0232] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
and
[0233] Y is CH.sub.2NH, NH(CO), or NMe(CO).
In other embodiments, compounds of the invention are compounds
wherein
##STR00059##
[0234] R.sub.2 is aryloxy;
[0235] R.sub.3 is CF.sub.3;
[0236] a is 0;
[0237] b is 1;
[0238] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0239] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0240] R.sub.7 is OH, OP(O).sub.3H.sub.2, or CO.sub.2H;
[0241] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
[0242] R.sub.8a and R.sub.8b are hydrogen; and
[0243] Y is CH.sub.2NH, NH(CO), or NMe(CO).
In yet other embodiments, compounds of the invention are compounds
wherein
##STR00060##
[0244] R.sub.2 is aryloxy;
[0245] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0246] R.sub.6 is hydrogen or alkyl;
[0247] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
and
##STR00061##
wherein
##STR00062##
indicate points of attachment. In yet other embodiments, compounds
of the invention are compounds wherein
##STR00063##
[0248] R.sub.2 is aryloxy;
[0249] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0250] R.sub.6 is hydrogen or alkyl;
[0251] R.sub.7 is OH, OP(O).sub.3H.sub.2, or CO.sub.2H;
[0252] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
and
##STR00064##
wherein
##STR00065##
indicate points of attachment. In further embodiments, compounds of
the invention are compounds wherein
##STR00066##
[0253] R.sub.2 is aryloxy;
[0254] R.sub.3 is CF.sub.3;
[0255] a is 0;
[0256] b is 1;
[0257] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0258] R.sub.6 is hydrogen or alkyl;
[0259] R.sub.7 is OH, OP(O).sub.3H.sub.2, or CO.sub.2H;
[0260] X is CH.sub.2, NH, N-alkyl, --O--, --S--, or --C(O)--;
[0261] R.sub.8a and R.sub.8b are hydrogen; and
##STR00067##
wherein
##STR00068##
indicate points of attachment.
[0262] In further aspects, the present invention is drawn to a
compound of formula II.
##STR00069##
[0263] or a pharmaceutically acceptable salt thereof, wherein:
[0264] R.sub.1a is aryl or heteroaryl, either of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halo, alkyl, hydroxyl, or --O-alkyl;
[0265] R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl;
[0266] R.sub.3 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylenesulfonyl, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl;
[0267] a and b are each independently 0, 1, 2, or 3;
##STR00070##
are each independently phenyl or pyridyl;
[0268] R.sub.4 is hydrogen, cyano, alkyl, aryl, heteroaryl,
alkylene-OH, aryl, alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H;
[0269] R.sub.5 and R.sub.6 are each independently selected from the
group consisting of hydrogen, alkyl, alkylene-OH, aryl,
alkylene-O-alkyl, --CO.sub.2H, CO.sub.2-alkyl, alkylene-OC(O)alkyl,
cycloalkyl, heterocyclo, --C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl,
--C(O)--Oalkyl, --C(O)--Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or
[0270] R.sub.5 and R.sub.6, together with the nitrogen to which
they are attached, may form a 3, 4, 5, or 6-membered saturated or
unsaturated ring, optionally containing 1 or 2 additional
heteroatoms selected from O, S, NH, or N-alkyl, and optionally
substituted on carbon with halogen, alkyl, hydroxyl, or alkoxy;
[0271] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, --OPO.sub.2(S)NR.sub.p1R.sub.p2,
and --C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein
[0272] Z' is hydroxyl or halogen;
[0273] Z'' is H or halogen;
[0274] R.sub.p1 and R.sub.p2 at each occurrence are independently
hydrogen, C.sub.1-C.sub.6-alkyl, or aryl;
[0275] X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3--,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, O, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein
[0276] R.sub.x1 and R.sub.x2 at each occurrence are independently
selected from the group consisting of hydrogen, hydroxyl, halogen,
alkyl, --O-alkyl, alkylyene-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and
CO.sub.2-alkyl, any of which may be optionally substituted on
carbon with halogen; or taken together R.sub.x1 and R.sub.x2 may
form a 3, 4, 5, or 6 membered ring optionally containing 1 or 2
heteroatoms selected from O, S, NH, or N-alkyl, which may itself be
substituted on carbon with halogen, hydroxyl, or alkyl;
[0277] R.sub.x3 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0278] n is an integer from 0 to 4; and
##STR00071##
[0279] is a heteroaryl ring containing up to four heteroatoms
selected from N, O, or S, optionally substituted on carbon with
halogen or alkyl, wherein
[0280] Y.sub.1 is N, S, or O;
[0281] Y.sub.2 and Y.sub.3 are each independently C, N, O, or S;
provided that when
##STR00072##
contains an N--H, that hydrogen may be replaced with alkyl;
[0282] Y.sub.4 is C or N; and
[0283] R.sub.8a and R.sub.8b are each independently hydrogen,
halogen, alkyl, or taken together with the carbon to which they are
attached, may form a 3, 4, 5, or 6-membered ring, optionally
containing 1 or 2 heteroatoms selected from NH, N-alkyl, O, or S,
and optionally substituted on carbon with halogen, or alkyl.
[0284] It is to be understood that when the values for a and b are
less than the total number of open substituents on the ring, the
remainder of the substituents are hydrogen.
That is, if b is 1, the remaining three substituents on
##STR00073##
are hydrogen.
[0285] In some embodiments, R.sub.1a is phenyl.
[0286] In some embodiments, a is 0. In other embodiments, a is
1.
[0287] In some embodiments, b is 1.
[0288] In some embodiments,
##STR00074##
In other embodiments,
##STR00075##
[0289] In some embodiments,
##STR00076##
In other embodiments,
##STR00077##
[0290] As provided above, the compounds of formula II include an
SEM. The SEM may be a halogen such as F or Cl. It may also be a
halo-substituted alkyl group such as CF.sub.3, CF.sub.2CF.sub.3,
CF.sub.2CF.sub.2CF.sub.3, CFHCF.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CF.sub.3, CHCl.sub.2, or CH.sub.2Cl. It may also be
cyano.
[0291] Thus, in some embodiments, R.sub.3 is trifluoromethyl. In
some embodiments, R.sub.3 is methyl. In other embodiments, R.sub.3
is dimethylamino. In other embodiments, R.sub.3 is fluoro. In other
embodiments, R.sub.3 is chloro. In other embodiments, R.sub.3 is
bromo. In other embodiments, R.sub.3 is cyano. In other
embodiments, R.sub.3 is dimethylamino.
[0292] In some embodiments, R.sub.4 is hydrogen. In other
embodiments, R.sub.4 is methyl. In other embodiments, R.sub.4 is
hydroxymethyl.
[0293] In some embodiments, R.sub.5 and R.sub.6 are independently
hydrogen.
[0294] In some embodiments, R.sub.7 is OH. In other embodiments,
R.sub.7 is CO.sub.2H. In other embodiments, R.sub.7 is CO.sub.2Me
or CO.sub.2Et. Another In other embodiments, R.sub.7 is
CO.sub.2-phenyl. In other embodiments, R.sub.7 is
--OP(O).sub.3H.sub.2.
[0295] In some embodiments, X is CH.sub.2. In other embodiments, X
is NH or N-alkyl. In other embodiments, X is O. In other
embodiments, X is S, SO, or SO.sub.2. In other embodiments, X is
CO.
[0296] In some embodiments, Y is
##STR00078##
In other embodiments, Y is
##STR00079##
In other embodiments, Y is
##STR00080##
In other embodiments, Y is
##STR00081##
In other embodiments, Y is
##STR00082##
In some embodiments, Y is
##STR00083##
In other embodiments, Y is
##STR00084##
In other embodiments, Y is
##STR00085##
In other embodiments, Y is
##STR00086##
In some embodiments, Y is
##STR00087##
In other embodiments, Y is
##STR00088##
In other embodiments, Y is
##STR00089##
In other embodiments, Y is
##STR00090##
Another specific value for Y is
##STR00091##
In some embodiments,
##STR00092##
In other embodiments, Y is
##STR00093##
In other embodiments, Y is
##STR00094##
In other embodiments, Y is
##STR00095##
In the above structures, R can be hydrogen or alkyl, and
##STR00096##
indicates a point of attachment.
[0297] In some embodiments, R.sub.8a is hydrogen.
[0298] In some embodiments, R.sub.8b is hydrogen.
In some embodiments, compounds of the invention are compounds
wherein
[0299] R.sub.1a is phenyl;
[0300] R.sub.4 is hydrogen, alkyl, or alkyl-OH;
[0301] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0302] R.sub.7 is selected from the group consisting of --OH,
alkyl-OH, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCOO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and
--C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2; wherein
[0303] X is CR.sub.x1R.sub.x2NR.sub.x3, O, --S--, --S(O)--,
--S(O).sub.2--, --OS(O).sub.2--, --OS(O).sub.2O--, --C(O)--, or
--C(O)O--; wherein
[0304] R.sub.x3 is hydrogen or alkyl;
In other embodiments, compounds of the invention are compounds
wherein
[0305] R.sub.1a is phenyl;
[0306] R.sub.4 is hydrogen, alkyl, hydroxy-alkyl, aryl,
alkoxy-alkyl, or carboxy-alkyl;
[0307] R.sub.5 and R.sub.6 are each independently hydrogen, alkyl,
hydroxy-alkyl, aryl, alkoxy-alkyl, --C(O)-alkyl, C(O)-aryl,
--C(O)--Oalkyl, or C(O)--Oaryl;
[0308] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
oh the same carbon may be taken together to from C.dbd.O;
wherein
[0309] R.sub.p1R.sub.p2 are each independently hydrogen, alkyl, or
aryl; and
[0310] X is CR.sub.x1R.sub.x2, NR.sub.x3, O, --S--, --S(O)--,
--S(O).sub.2--, or --C(O)--, wherein R.sub.x1, R.sub.x2, and
R.sub.x3 are each independently hydrogen or alkyl. In other
embodiments, compounds of the invention are compounds wherein
[0311] R.sub.1a is phenyl;
##STR00097##
[0312] R.sub.1 is aryloxy;
[0313] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0314] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl; and
[0315] R.sub.8a and R.sub.8b are hydrogen;
In yet other embodiments, compounds of formula II are compounds of
formula II-1.
##STR00098##
[0316] and pharmaceutically acceptable salts thereof.
In other embodiments, compounds of formula II are compounds of
formula II-2A or II-2B.
##STR00099##
[0317] and pharmaceutically acceptable salts thereof.
In further embodiments, compounds of formula II are compounds of
formula II-3A or II-3B.
##STR00100##
[0318] and pharmaceutically acceptable salts thereof.
In other embodiments, compounds of formula II are compounds of
formula II-4A or II-4B.
##STR00101##
[0319] and pharmaceutically acceptable salts thereof.
In still other embodiments, compounds of formula II are compounds
of formula II-5A or II-5B.
##STR00102##
[0320] and pharmaceutically acceptable salts thereof.
In other embodiments, compounds of formula II are compounds of
formula II-6A or II-6B.
##STR00103##
[0321] and pharmaceutically acceptable salts thereof.
In further embodiments, compounds of formula II are compounds of
formula II-7A or II-7B.
##STR00104##
[0322] and pharmaceutically acceptable salts thereof.
In other embodiments, compounds of formula II are compounds of
formula II-8A or II-8B.
##STR00105##
[0323] and pharmaceutically acceptable salts thereof.
[0324] In still other aspects, the present invention is drawn to a
compound of formula III.
##STR00106##
[0325] or a pharmaceutically acceptable salt thereof, wherein:
[0326] R.sub.1a is aryl or heteroaryl, either of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halo, alkyl, hydroxyl, or --O-alkyl;
[0327] R.sub.2 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylSO.sub.2, alkylSO, aralkylSO.sub.2, aralkylSO,
alkylene-CO-amino, alkylene-CO-alkylamino,
alkylene-CO-dialkylamino, alkylene-NH--CO.sub.2H,
alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl, --OH, --C(O)-alkyl,
--C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino, --CO-dialkylamino,
amino, alkylamino, and dialkylamino, any of which may be optionally
substituted on carbon with 1, 2, or 3 groups selected from halo,
alkyl, OH, or --O-alkyl;
[0328] R.sub.3 is halogen, cyano, alkyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, --O-alkyl,
--O-aryl, --O-heteroaryl, aralkoxy, heteroaralkoxy, --S-alkyl,
alkylene-O-alkyl, alkylene-CO.sub.2H, alkylene-CO.sub.2alkyl,
alkylSO.sub.2, alkylenesulfonyl, alkylene-CO-amino,
alkylene-CO-alkylamino, alkylene-CO-dialkylamino,
alkylene-NH--CO.sub.2H, alkylene-NH--CO.sub.2alkyl-CO.sub.2alkyl,
--OH, --C(O)-alkyl, --C(O)O-alkyl, --CONH.sub.2, --CO-alkylamino,
--CO-dialkylamino, amino, alkylamino, and dialkylamino, any of
which may be optionally substituted on carbon with 1, 2, or 3
groups selected from halo, alkyl, OH, or --O-alkyl;
[0329] a is 0, 1, 2, or 3;
[0330] b is 1, 2, or 3;
##STR00107##
[0331] are each independently phenyl or pyridyl;
[0332] R.sub.4 is hydrogen, cyano, alkyl, aryl, heteroaryl,
alkylene-OH, aryl, alkylene-O-alkyl, --CO.sub.2H, --CO.sub.2-alkyl,
alkylene-CO.sub.2H, or alkylene-CO.sub.2-alkyl, alkylene-OC(O)R
wherein R is hydrogen or alkyl; cycloalkyl, heterocycloalkyl,
alkylene-NH.sub.2, alkylene-alkylamino, or alkylene-dialkylamino,
any of which may be optionally substituted on carbon with 1, 2, or
3 groups selected from OH, CO.sub.2H, CO.sub.2alkyl, halogen,
amino, alkylamino, dialkylamino, --O-alkyl, alkylene-O-alkyl,
alkylene-OH, or alkylene-CO.sub.2H;
[0333] R.sub.5 and R.sub.6 are each independently selected from the
group consisting of hydrogen, alkyl, alkylene-OH, aryl,
alkylene-O-alkyl, --CO.sub.2H, CO.sub.2-alkyl, alkylene-OC(O)alkyl,
cycloalkyl, heterocyclo, --C(O)-alkyl, --C(O)-aryl, C(O)-aralkyl,
--C(O)--Oalkyl, --C(O)--Oaryl, --C(O)--Oaralkyl, alkylene-amino,
alkylene-alkylamino, and alkylene-dialkylamino, any of which may be
optionally substituted on carbon with halogen, alkyl, hydroxyl,
CO.sub.2H, CO.sub.2alkyl or alkoxy; or
[0334] R.sub.5 and R.sub.6, together with the nitrogen to which
they are attached, may form a 3, 4, 5, on 6-membered saturated or
unsaturated ring, optionally containing 1 or 2 additional
heteroatoms selected from O, S, NH, or N-alkyl, and optionally
substituted on carbon with halogen, alkyl, hydroxyl, or alkoxy;
[0335] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, --OPO.sub.2(S)NR.sub.p1R.sub.p2,
and --C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, and
alkylene-C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O; and
wherein
[0336] Z' is hydroxyl or halogen;
[0337] Z'' is H or halogen;
[0338] R.sub.p1 and R.sub.p2 at each occurrence are independently
hydrogen, C.sub.1-C.sub.6-alkyl, or aryl;
[0339] X is CR.sub.x1R.sub.x2, NR.sub.x3,
--(CR.sub.x1R.sub.x2).sub.nNR.sub.x3,
--NR.sub.x3(CR.sub.x1R.sub.x2).sub.n--, O, --S--,
--(CR.sub.x1R.sub.x2).sub.nS--, --S(CR.sub.x1R.sub.x2).sub.n--,
--S(O)--, --(CR.sub.x1R.sub.x2).sub.nS(O)--,
--S(O)(CR.sub.x1R.sub.x2).sub.n--, --S(O).sub.2--,
--(CR.sub.x1R.sub.x2).sub.nS(O).sub.2--,
--S(O).sub.2(CR.sub.x1R.sub.x2).sub.n--, --C(O)--,
--(CR.sub.x1R.sub.x2).sub.nC(O)--,
--C(O)(CR.sub.x1R.sub.x2).sub.n--, --C(O)O--,
--(CR.sub.x1R.sub.x2).sub.nC(O)O--, and
--C(O)O(CR.sub.x1R.sub.x2).sub.n--; wherein
[0340] R.sub.x1 and R.sub.x2 at each occurrence are independently
selected from the group consisting of hydrogen, hydroxyl, halogen,
alkyl, --O-alkyl, alkylyene-O-alkyl, alkyl-SO.sub.2, CO.sub.2H, and
CO.sub.2-alkyl, any of which may be optionally substituted on
carbon with halogen; or taken together R.sub.x1 and R.sub.x2 may
form a 3, 4, 5, or 6 membered ring optionally containing 1 or 2
heteroatoms selected from O, S, NH, or N-alkyl, which may itself be
substituted on carbon with halogen, hydroxyl, or alkyl;
[0341] R.sub.x3 at each occurrence is selected from the group
consisting of hydrogen and alkyl;
[0342] n is an integer from 0 to 4;
[0343] Y is --CH.sub.2NR'''--, --CH.sub.2NR'''(CO)--, --CHFNR'''--,
--CHFNR'''(CO)--, --CF.sub.2NR'''--, --CF.sub.2NR'''(CO)--,
--CH.sub.2(CO)--, --CHF(CO)--, --CF.sub.2(CO)--, --(CO)CF.sub.2--,
--CH.sub.2(CHOH)--, --CHF(CHOH)--, --CF.sub.2(CHOH)--,
--(CHOH)CF.sub.2--, --NH(CO)--, --(CO)--, --(CO).sub.2--, --O--,
--S--, --SO--, --SO.sub.2--, --CH.sub.2O--, --CH.sub.2CH.sub.2O--,
--CH.sub.2OCH.sub.2--, --OCH.sub.2O--, --CH.sub.2S--,
--CH.sub.2SO--, --CH.sub.2SO.sub.2--, --CHFO--, --CHFS--,
--CHFSO--, --CHFSO.sub.2--, --CF.sub.2O--, --CF.sub.2S--,
--CF.sub.2SO--, --CF.sub.2SO.sub.2--, --NR'''SO.sub.2--,
--CF.sub.2--, --CF.sub.2CF.sub.2--, --CF.sub.2CF.sub.2CF.sub.2--,
wherein R''' is H or alkyl; and
[0344] R.sub.8a and R.sub.8b are each independently hydrogen,
halogen, alkyl, or taken together with the carbon to which they are
attached, may form a 3, 4, 5, or 6-membered ring, optionally
containing 1 or 2 heteroatoms selected from NH, N-alkyl, O, or S,
and optionally substituted on carbon with halogen, or alkyl.
[0345] It is to be understood that when the values for a and b are
less than the total number of open substituents on the ring, the
remainder of the substituents are hydrogen.
That is, if b is 1, the remaining three substituents on
##STR00108##
are hydrogen.
[0346] In some embodiments, R.sub.1a is phenyl.
[0347] In some embodiments, a is 0. In other embodiments, a is
1.
[0348] In some embodiments, b is 1.
[0349] In some embodiments,
##STR00109##
In other embodiments,
##STR00110##
[0350] In some embodiments,
##STR00111##
In other embodiments,
##STR00112##
[0351] As provided above, the compounds of formula III include an
SEM. The SEM may be a halogen such as F or Cl. It may also be a
halo-substituted alkyl group such as CF.sub.3, CF.sub.2CF.sub.3,
CF.sub.2CF.sub.2CF.sub.3, CFHCF.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CF.sub.3, CHCl.sub.2, or CH.sub.2Cl. It may also be
cyano.
[0352] Thus, in some embodiments, R.sub.3 is trifluoromethyl. In
some embodiments, R.sub.3 is methyl. In other embodiments, R.sub.3
is dimethylamino. In other embodiments, R.sub.3 is fluoro. In other
embodiments, R.sub.3 is chloro. In other embodiments, R.sub.3 is
bromo. In other embodiments, R.sub.3 is cyano. In other
embodiments, R.sub.3 is dimethylamino.
[0353] In some embodiments, R.sub.4 is hydrogen. In other
embodiments, R.sub.4 is methyl. In other embodiments, R.sub.4 is
hydroxymethyl.
[0354] In some embodiments, R.sub.5 and R.sub.6 are independently
hydrogen.
[0355] In some embodiments, R.sub.7 is OH. In other embodiments,
R.sub.7 is CO.sub.2H. In other embodiments, R.sub.7 is CO.sub.2Me
or CO.sub.2Et. Another In other embodiments, R.sub.7 is
CO.sub.2-phenyl. In other embodiments, R.sub.7 is
--OP(O).sub.3H.sub.2.
[0356] In some embodiments, X is CH.sub.2. In other embodiments, X
is NH or N-alkyl. In other embodiments, X is O. In other
embodiments, X is S, SO, or SO.sub.2. In other embodiments, X is
CO.
[0357] In some embodiments, Y is CH.sub.2. In other embodiments, Y
is CH.sub.2NH. In other embodiments, Y is NH(CO). In other
embodiments, Y is NMe(CO). In other embodiments, Y is C.dbd.O.
[0358] In some embodiments,
##STR00113##
wherein
##STR00114##
indicate points of attachment. In some embodiments,
##STR00115##
[0359] In some embodiments, R.sub.8a is hydrogen.
[0360] In some embodiments, R.sub.8b is hydrogen.
In some embodiments, compounds of the invention are compounds
wherein
[0361] R.sub.2 is alkyl, aryl, heteroaryl, aralkoxy, or
heteroaralkoxy.
[0362] R.sub.4 is hydrogen, alkyl, or alkyl-OH;
[0363] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl;
[0364] R.sub.7 is selected from the group consisting of --OH,
alkyl-OH, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and
--C(Z')(Z'')PO.sub.3R.sub.p1R.sub.p2; wherein
[0365] X is CR.sub.x1R.sub.x2, NR.sub.x3, O, --S--, --S(O)--,
--S(O).sub.2--, --OS(O).sub.2--, --OS(O).sub.2O--, --C(O)--, or
--C(O)O--; wherein
[0366] R.sub.x3 is hydrogen or alkyl;
In other embodiments, compounds of the invention are compounds
wherein
[0367] R.sub.2 is hydrogen, alkyl, or aryloxy;
[0368] R.sub.4 is hydrogen, alkyl, hydroxy-alkyl, aryl,
alkoxy-alkyl, or carboxy-alkyl;
[0369] R.sub.5 and R.sub.6 are each independently hydrogen, alkyl,
hydroxy-alkyl, aryl, alkoxy-alkyl, --C(O)-alkyl, C(O)-aryl,
--C(O)--Oalkyl, or C(O)--Oaryl;
[0370] R.sub.7 is selected from the group consisting of alkyl,
--OH, --O-alkyl, --CO.sub.2H, --C(O)O-alkyl, --C(O)O-aryl,
--CH.sub.2.dbd.CHCO.sub.2H, --CH.sub.2.dbd.CHC(O)O-alkyl,
--CH.sub.2.dbd.CHC(O)O-aryl, --OPO.sub.2R.sub.p1R.sub.p2,
--OPO.sub.3R.sub.p1R.sub.p2, --CH.sub.2PO.sub.3R.sub.p1R.sub.p2,
--OPO.sub.2(S)R.sub.p1R.sub.p2, and alkylene-OH,
alkylene-CO.sub.2H, alkylene-C(O)O-alkyl, alkylene-C(O)O-aryl,
alkylene-CH.dbd.CHCO.sub.2H, alkylene-CH.sub.2.dbd.CHC(O)O-alkyl,
alkylene-CH.sub.2.dbd.CHC(O)O-aryl,
alkylene-OPO.sub.2R.sub.p1R.sub.p2,
-alkylene-OPO.sub.3R.sub.p1R.sub.p2,
alkylene-PO.sub.3R.sub.p1R.sub.p2,
alkylene-OPO.sub.2(S)R.sub.p1R.sub.p2, any of which may be
optionally substituted on carbon with 1, 2, or 3 groups selected
from halogen, alkyl, hydroxyl, carboxy, or alkoxy, or any 2 groups
on the same carbon may be taken together to from C.dbd.O;
wherein
[0371] R.sub.p1R.sub.p2 are each independently hydrogen, alkyl, or
aryl; and
[0372] X is CR.sub.x1R.sub.x2, NR.sub.x3, O, --S--, --S(O)--,
--S(O).sub.2--, or --C(O)--, wherein R.sub.x1, R.sub.x2, and
R.sub.x3 are each independently hydrogen or alkyl.
In still other embodiments, compounds of the invention are
compounds wherein
##STR00116##
[0373] R.sub.1a is aryl;
[0374] R.sub.4 is hydrogen, alkyl, or alkylene-OH;
[0375] R.sub.5 and R.sub.6 are each independently hydrogen or
alkyl; and
[0376] R.sub.8a and R.sub.8 b are hydrogen;
In further embodiments, compounds of formula III are compounds of
formula III-1.
##STR00117##
[0377] and pharmaceutically acceptable salts thereof.
In other embodiments, compounds of formula III are compounds of
formula III-2A or III-2B.
##STR00118##
[0378] and pharmaceutically acceptable salts thereof.
In some embodiments, compounds of formula III are compounds of
formula III-3A, III-3B, III-3C, or III-3D.
##STR00119##
[0379] and pharmaceutically acceptable salts thereof.
In other embodiments, compounds of formula III are compounds of
formula III-4A, III-4B, III-4C, or III-4D.
##STR00120##
[0380] and pharmaceutically acceptable salts thereof.
In some embodiments, compounds of the present invention include
compounds listed in the following table:
##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127##
wherein n is 0, 1, or 2 for the above compounds, as well as
pharmaceutically acceptable salts, phosphate derivatives, phosphate
mimics, or phosphate precursor analogs thereof.
[0381] In some embodiments of the present invention, R.sub.2 is not
aryl. In other embodiments, of the present invention, X is not
--O--. In still other embodiments of the invention, the compound is
not a compound as described in WO 06/020951, published Feb. 23,
2006. In still other embodiments, the compound is not a compound as
described in U.S. Publication No. 20060223866, published Oct. 5,
2006.
Preparation of Invention Compounds
[0382] The general approaches for the synthesis of invention
compounds are summarized in Scheme 1 and 2. Reaction of substituted
3-mercaptophenol with substituted 4-fluoroacetophenone 1 and benzyl
bromide afforded the thio-ether-acetophenone intermediate 2. The
thio-ether-acetophenone 2 was then converted to the
.alpha.-bromo-acetophenone 3 by reaction with tetrabutylammonium
tribromide. Reaction of the bromo-acetophenone with Boc-protected
.alpha.-amino acids followed by cyclizatioin with ammonium acetate
afforded the imidazole analog 4. Removal of the Boc group provided
the TFA salt of the final compound 5 in good yield.
##STR00128##
[0383] Reaction of substituted benzoate 6 with 3-mercaptophenol
followed by benzyl bromide afforded the thio-either 7 which upon
refluxing with hydrazine in ethylene glycol provided hydrazide 8.
Hydrazide 8 was then coupled with orthogonally protected
.alpha.-methylserine 9 and cyclized to thiadiazole 11 by reaction
with Lawesson's reagent. Thiadiazole 11 deprotection afforded the
final alcohol 12 in reasonable overall yield.
##STR00129##
Biological Activity of Invention Compounds
[0384] Lymphopenia Assay
[0385] Several compounds were evaluated for the ability to induce
lymphopenia in mice. Male C57B1/6 mice were divided into three
groups. The control group received the 3% BSA vehicle only. The
other two groups received a single dose of test compound in vehicle
by oral administration (PO) and intravenous administration (IV),
respectively. After 6 hours, the mice were anesthesized with
isoflurane and approximately 250 .mu.L of blood was removed from
the retroorbital sinus and collected in an EDTA microtainer, mixed
with an anticoagulant and placed on a tilt table until complete
blood count (CBC) analysis. Table 1 and FIG. 1 illustrate the
results of this lymphopenia assay performed with S1P-1 agonists. It
can be seen from these results that oral administration (10 mg/kg)
of these compounds induced significant lymphopenia compared to the
control.
TABLE-US-00001 TABLE 1 Structures of Compounds A through D, tested
as S1P1 receptor agonists. Structure Identification ##STR00130## A
##STR00131## B ##STR00132## C ##STR00133## D
[0386] Interaction of Invention Compounds with SIP Receptors
[0387] In certain embodiments, the compounds of the invention
selective for the S1P-1 receptor as compared to one or more of the
other S1P receptors. For example, one set of compounds includes
compounds which are selective for the S1P-1 receptor relative to
the S1P-3 receptor.
[0388] A compound is "selective" for the S1P-1 receptor relative to
a second receptor, if the IC.sub.50 of the compound for the second
receptor is at least two-fold greater than the IC.sub.50 for the
S1P-1 receptor. The IC.sub.50 of a compound is determined using the
[.sup.33P]sphingosine 1-phosphate binding assay, as described in
Davis, M. D. et al., Sphingosine 1-Phosphate Analogs as Receptor
Antagonists. J. Biol. Chem. (2005) 280:9833-9841, the entire
contents of which are incorporated herein by this reference.
[0389] Compounds selective for the S1P-1 receptor can be agonists
of the S1P-1receptor, significantly weaker agonists of one or more
other receptors and/or antagonists of one or more other receptors.
The terms "agonist" or "S1P-1 receptor agonist" as used herein
include the compounds described herein which bind to and/or agonize
the S1P-1 receptor. The EC.sub.50 of a compound is determined using
the .sup.35S-GTP.gamma.S binding assay, as described in WO
03/061567, the entire contents of which are incorporated herein by
reference. For example, compound 7a had an EC.sub.50 of 6.9 nM.
[0390] In one embodiment, the S1P receptor agonists have an
IC.sub.50 for the S1P-1 receptor of about 100 nM-0.25 nM, about 50
nM-0.25 nM, about 25 nM-0.5 nM, about 100 nM or less, about 75 nM
or less, about 50 nM or less, about 40 nM or less, about 30 nM or
less, about 20 nM or less, about 10 nM or less, about 5 nM or less,
about 1 nM or less, about 0.5 nM or less, or about 0.25 nM or less.
The compounds' IC.sub.50 for the S1P-1 receptor can be measured
using the binding assays described in Example 13 or those described
in WO 03/061567.
[0391] Ranges intermediate to the above recited values are also
intended to be part of this invention. For example, ranges using a
combination of any of the above recited values as upper and/or
lower limits are intended to be included.
[0392] In a further embodiment, the S1P receptor agonist has an
IC.sub.50 value for the S1P-3 receptor of about 10 nM-10,000 nM,
about 100 nM-5000 nM, about 100 nM-3000 nM, about 10 nM or greater,
about 20 nM or greater, about 40 nM or greater, about 50 nM or
greater, about 75 nM or greater, or about 100 nM or greater. In
another embodiment, the S1P compound of the invention binds the
S1P-3 receptor with an IC.sub.50 of 1000 nM or greater, 2000 nM or
greater, 3000 nM or greater, 5000 nM or greater, 10,000 nM or
greater. The IC.sub.50 for of S1P-3 receptor can be measured using
the binding assays described herein or those described in WO
03/061567.
[0393] In addition, it should be understood that the ranges
intermediate to the above recited values are also intended to be
part of this invention. For example, ranges using a combination of
any of the above recited values as upper and/or lower limits are
intended to be included.
[0394] In yet another embodiment, the S1P receptor agonists
described herein have an IC.sub.50 value for the S1P-1 receptor
that is about 5-fold lower, about 10-fold lower, about 20-fold
lower, about 50-fold lower, about 100-fold lower, about 200-fold
lower, about 500-fold lower or about 1000-fold lower than their
IC.sub.50 value for the S1P-3 receptor.
[0395] Ranges intermediate to the above recited values are also
intended to be part of this invention. For example, ranges using a
combination of any of the above recited values as upper and/or
lower limits are intended to be included.
[0396] The ability of several of the compounds described herein to
bind to the S1P-1 or S1P-3 receptor was tested as follows.
[0397] For the membrane preparation, plasmid DNA was transfected
into HEK 293 T cells using the FuGENE 6 transfection protocol
Briefly, subconfluent monolayers of HEK 293 T cells were
transfected with the DNA mixture containing FuGENE 6 (using a 1:3
ratio). The dishes containing the cells were then placed in a
tissue culture incubator (5% CO.sub.2, 37.degree. C.). The cells
were harvested 48 hours after addition of the DNA by scraping in
HME buffer (in mM: 20 HEPES, 5 MgCl.sub.2, 1 EDTA, pH 7.4, 1 mM
PMSF) containing 10% sucrose on ice, and disrupted using aDounce
homogenizer. After centrifugation at 800.times.g, the supernatant
was diluted with HME without sucrose and centrifuged at
17,000.times.g for 1 hour. This crude membrane pellet was
resuspended in HME with sucrose, aliquoted, and snap-frozen by
immersion in liquid nitrogen. The membranes were stored at
-70.degree. C. Protein concentration was determined
spectroscopically by Bradford protein assay.
[0398] For the binding assay, [.sup.33P]sphingosine 1-phosphate
(obtained from American Radiolabeled Chemicals, Inc) was added to
membranes in 200 .mu.L in 96-well plates with assay concentrations
of 2.5 pM [.sup.33P]sphingosine 1-phosphate, 4 mg/mL BSA, 50 mM
HEPES, pH 7.5, 100 mM NaCl, 5 mM MgCl2, and 5 .mu.g of protein.
Binding was performed for 60 minutes at room temperature with
gentle mixing and terminated by collecting the membranes onto GF/B
filter plates. After drying the filter plates for 10 minutes, 50
.mu.L of Microscint 40 was added to each well, and filter-bound
radionuclide was measured on a Packard Top Count. Nonspecific
binding was defined as the amount of radioactivity remaining in the
presence of excess of unlabeled S1P. The results for the foregoing
binding assays are presented in Table 2 provided below.
TABLE-US-00002 TABLE 2 IC50 Values for Binding to S1P1 or S1P3
Receptors IC50 IC50 IC50/IC50 Structure (S1P-1) (S1P-3)
(S1P-3/S1P-1) ##STR00134## **** *** +++ ##STR00135## **** ** +++
##STR00136## **** * ##STR00137## **** *** ++ ##STR00138## *** * Key
IC.sub.50 * very low receptor binding affinity (IC.sub.50 >
10,000 nM) ** low receptor binding affinity (10,000 nM .gtoreq.
IC.sub.50 > 1,000 nM) *** moderate receptor binding affinity
(1,000 nM .gtoreq. IC.sub.50 > 100 nM) **** high receptor
binding affinity (100 nM .gtoreq. IC.sub.50 .gtoreq. 0.001 nM) +
moderate receptor selectivity (>100 fold) ++ good receptor
selectivity (>100-1,000 fold) +++ great receptor selectivity
(>1,000 fold)
Methods of Using Invention Compounds
[0399] The compounds of the invention have been determined to be
useful in the treatment of S1P associated disorders. Accordingly,
in one embodiment, the invention relates to a method for treating a
subject suffering from a S1P associated disorder, comprising
administering to a subject an effective amount of a compound of the
invention; that is, a compound of formula I or compounds otherwise
described herein, such that the subject is treated for a S1P
associated disorder.
[0400] The term "S1P associated disorder" includes disorders,
diseases or conditions which are associated with or caused by a
misregulation in S1P receptor function and/or signaling or S1P
receptor ligand function. The term also includes diseases,
disorders or conditions which can be treated by administering to a
subject an effective amount of a S1P receptor agonist. Such
disorders include disorders that are associated with an
inappropriate immune response and conditions associated with an
overactive immune response, e.g., autoimmune diseases.
[0401] "Treatment", or "treating" as used herein, is defined as the
application or administration of a therapeutic agent such as a
compound of formula I to a subject who has a S1P associated
disorder as described herein, with the purpose to cure, heal,
alleviate, delay, relieve, alter, remedy, ameliorate, improve or
affect the disease or disorder, or symptoms of the disease or
disorder. The term "treatment" or "treating" is also used herein in
the context of administering agents prophylactically.
[0402] An additional embodiment of the invention pertains to a
method for treating a subject suffering from a S1P associated
disorder, comprising administering to a subject a compound, such
that the subject is treated for a S1P associated disorder by a
compound of the invention; that is, a compound of formulae I or
compounds otherwise described herein.
[0403] The present invention is also directed to a method of
selectively treating a S1P associated disorder, comprising
administering to a subject an effective amount of a compound of the
invention or compounds otherwise described herein, such that the
subject is selectively treated for a S1P associated disorder. In
certain embodiments, the S1P associated disorder is a S1P-1
associated disorder. In a particular embodiment, the S1P-1
associated disorder is selectively treated as compared with a S1P-3
associated disorder.
[0404] Another embodiment of the invention is a method of
selectively treating a S1P associated disorder, comprising
administering to a subject a compound, such that the subject is
selectively treated for a sphingosine 1-phosphate associated
disorder by a compound of the invention or compounds otherwise
described herein. In certain embodiments, the S1P associated
disorder is a S1P-1 associated disorder. In a particular
embodiment, the S1P-1 associated disorder is selectively treated as
compared with a S1P-3 associated disorder.
[0405] In another embodiment, the present invention provides a
method of treating a condition associated with an activated immune
system. Such diseases or disorders include rejection of
transplanted organs, tissue or cells; graft-versus-host diseases
brought about by transplantation; autoimmune syndromes including
rheumatoid arthritis; systemic lupus erythematosus;
antiphospholipid syndrome; Hashimoto's thyroiditis; lymphocytic
thyroiditis; multiple sclerosis; myasthenia gravis; type I
diabetes; uveitis; episcleritis; scleritis; Kawasaki's disease,
uveo-retinitis; posterior uveitis; uveitis associated with Behcet's
disease; uveomeningitis syndrome; allergic encephalomyelitis;
chronic allograft vasculopathy; post-infectious autoimmune diseases
including rheumatic fever and post-infectious glomerulonephritis;
inflammatory and hyperproliferative skin diseases; psoriasis;
psoriatic arthritis; atopic dermatitis; myopathy; myositis;
osteomyelitis; contact dermatitis; eczematous dermatitis;
seborrhoeic dermatitis; lichen planus; pemphigus; bullous
pemphigoid; epidermolysis bullosa; urticaria; angioedema;
vasculitis; erythema; cutaneous eosinophilia; acne; scleroderma;
alopecia areata; keratoconjunctivitis; vernal conjunctivitis;
keratitis; herpetic keratitis; dystrophia epithelialis corneas;
corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative
keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada
syndrome; sarcoidosis; pollen allergies; reversible obstructive
airway disease; bronchial asthma; allergic asthma; intrinsic
asthma; extrinsic asthma; dust asthma; chronic or inveterate
asthma; late asthma and airway hyper-responsiveness; bronchiolitis;
bronchitis; endometriosis; orchitis; gastric ulcers; ischemic bowel
diseases; inflammatory bowel diseases; necrotizing enterocolitis;
intestinal lesions associated with thermal burns; coeliac disease;
proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's
disease; ulcerative colitis; vascular damage caused by ischemic
diseases and thrombosis; atherosclerosis; fatty heart; myocarditis;
cardiac infarction; aortitis syndrome; cachexia due to viral
disease; vascular thrombosis; migraine; rhinitis; eczema;
interstitial nephritis; IgA-induced nephropathy; Goodpasture's
syndrome; hemolytic-uremic syndrome; diabetic nephropathy;
glomerulosclerosis; glomerulonephritis; tubulointerstitial
nephritis; interstitial cystitis; multiple myositis; Guillain-Barre
syndrome; Meniere's disease; polyneuritis; multiple neuritis;
myelitis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's
disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia;
hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune
hemolytic anemia; autoimmune thrombocytopenia; agranulocytosis;
pernicious anemia; megaloblastic anemia; anerythroplasia;
osteoporosis; fibroid lung; idiopathic interstitial pneumonia;
dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris;
photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis
nodosa; Huntington's chorea; Sydenham's chorea; myocardosis;
myocarditis; scleroderma; Wegener's granuloma; Sjogren's syndrome;
adiposis; eosinophilic fascitis; lesions of gingiva, periodontium,
alveolar bone, substantia ossea dentis; male pattern alopecia or
alopecia senilis; muscular dystrophy; pyoderma; Sezary's syndrome;
hypophysiti's; chronic adrenal insufficiency; Addison's disease;
ischemia-reperfusion injury of organs which occurs upon
preservation; endotoxin shock; pseudomembranous colitis; colitis
caused by drug or radiation; ischemic acute renal insufficiency;
chronic renal insufficiency; lung solid cancer; malignancy of
lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma;
psoriasis; pulmonary emphysema; cataracts; siderosis; retinitis
pigmentosa; senile macular degeneration; vitreal scarring; corneal
alkali burn; dermatitis erythema; ballous dermatitis; cement
dermatitis; gingivitis; periodontitis; sepsis; pancreatitis;
peripheral artery disease; carcinogenesis; solid cancer tumors;
metastasis of carcinoma; hypobaropathy; autoimmune hepatitis;
primary biliary cirrhosis; sclerosing cholangitis; partial liver
resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis;
hepatic failure; fulminant hepatic failure; late-onset hepatic
failure; "acute-on-chronic" liver failure.
[0406] As used herein, the term "subject" includes warm-blooded
animals, e.g., mammals, including humans, cats, dogs, horses,
bears, lions, tigers, ferrets, rabbits, mice, cows, sheep, pigs,
etc. In a particular embodiment, the subject is a primate. In a
specific embodiment, the primate is a human.
[0407] As used herein, the term "administering" to a subject
includes dispensing, delivering or applying a compound of the
invention in a pharmaceutical formulation (as described herein), to
a subject by any suitable route for delivery of the compound to the
desired location in the subject, including delivery by either the
parenteral or oral route, intramuscular injection,
subcutaneous/intradermal injection, intravenous injection, buccal
administration, topical delivery, transdermal delivery and
administration by the rectal, colonic, vaginal, intranasal or
respiratory tract route.
[0408] As used herein, the term "effective amount" includes an
amount effective, at dosages and for periods of time necessary, to
achieve the desired result; that is, sufficient to treat the
condition in a subject. An effective amount of a compound of the
invention, as defined herein, may vary according to factors such as
the disease state, age, and weight of the subject, and the ability
of the compound to elicit a desired response in the subject. Dosage
regimens may be adjusted to provide the optimum therapeutic
response. An effective amount is also one in which any toxic or
detrimental effects (such as side effects) associated with
administration of the compound are outweighed by the
therapeutically beneficial effects.
[0409] A therapeutically effective amount of a compound of the
invention (i.e., an effective dosage) may range from about 0.001 to
30 mg/kg body weight, for example, about 0.01 to 25 mg/kg body
weight, for example, about 0.1 to 20 mg/kg body weight. It is to be
understood that all values and ranges between those listed are
intended to be encompassed by the present invention. The skilled
artisan will appreciate that certain factors may influence the
dosage required to effectively treat a subject, including but not
limited to the severity of the disease or disorder, previous
treatments, the general health and/or age of the subject, and other
diseases present. Moreover, treatment of a subject with a
therapeutically effective amount of a compound of the invention can
include a single treatment or, for example, can include a series of
treatments. It will also be appreciated that the effective dosage
of the compound used for treatment may increase or decrease over
the course of a particular treatment.
[0410] The methods of the invention further include administering
to a subject a therapeutically effective amount of a compound of
the invention in combination with another pharmaceutically active
compound known to treat the disease or condition, e.g., an
immunomodulatory agent or an anti-inflammatory agent.
Pharmaceutically active compounds that may be used depend upon the
condition to be treated, but include as examples cyclosporin,
rapamycin, FK506, methotrexate, etanercept, infliximab, adalimumab,
non-steroidal anti-inflammatory agents,
cyclooxygenase-2-inhibitors, such as celecoxib and rofecoxib, and
corticosteroids. Other suitable compounds can be found in
Harrison's Principles of Internal Medicine, Thirteenth Edition,
Eds. T. R. Harrison et al. McGraw-Hill N.Y., N.Y.; and the
Physicians Desk Reference 50th Edition 1997, Oradell N.J., Medical
Economics Co., the complete contents of which are expressly
incorporated herein by reference. The compound of the invention and
the additional pharmaceutically active compound may be administered
to the subject in the same pharmaceutical composition or in
different pharmaceutical compositions (at the same time or at
different times).
Pharmaceutical Compositions Comprising Invention Compounds
[0411] The present invention also provides pharmaceutically
acceptable formulations
[0412] and compositions comprising one or more compounds of the
invention; that is, compounds of formula I or compounds otherwise
described herein. In certain embodiments, the compound of the
invention is present in the formulation in a therapeutically
effective amount; that is, an amount effective to treat a
S1P-associated disorder.
[0413] Accordingly, in one embodiment, the invention pertains to a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of the invention; that is, compounds of
formula I or compounds otherwise described herein, and a
pharmaceutically acceptable carrier.
[0414] In another embodiment, the invention is directed to a
packaged pharmaceutical composition comprising a container holding,
a therapeutically effective amount of a compound of the invention;
that is, compounds of formula I or compounds otherwise described
herein; and instructions for using the compound to treat a
sphingosine 1-phosphate associated disorder in a subject.
[0415] The term "container" includes any receptacle for holding the
pharmaceutical composition. For example, in one embodiment, the
container is the packaging that contains the pharmaceutical
composition. In other embodiments, the container is not the
packaging that contains the pharmaceutical composition, i.e., the
container is a receptacle, such as a box or vial that contains the
packaged pharmaceutical composition or unpackaged pharmaceutical
composition and the instructions for use of the pharmaceutical
composition. Moreover, packaging techniques are well known in the
art. It should be understood that the instructions for use of the
pharmaceutical composition may be contained on the packaging
containing the pharmaceutical composition, and as such the
instructions form an increased functional relationship to the
packaged product. However, it should be understood that the
instructions can contain information pertaining to the compound's
ability to perform its intended function, e.g., treating,
preventing, or reducing a SIP-associated disorder in a subject.
[0416] Another embodiment of the invention relates to a packaged
pharmaceutical
[0417] composition comprising a container holding a therapeutically
effective amount of a compound of the invention; that is, a
compound of formula I or compounds otherwise described herein, and
instructions for using the compound to selectively treat a
S1P-associated disorder in a subject.
[0418] Such pharmaceutically acceptable formulations typically
include one or more compounds of the invention as well as one or
more pharmaceutically acceptable carriers and/or excipients. As
used herein, "pharmaceutically acceptable carrier" includes any and
all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents, and the
like that are physiologically compatible. The use of such media and
agents for pharmaceutically active substances is well known in the
art. Except insofar as any conventional media or agent is
incompatible with the compounds of the invention, use thereof in
the pharmaceutical compositions is contemplated.
[0419] Supplementary pharmaceutically active compounds known to
treat transplant or autoimmune disease, i.e., immunomodulatory
agents and anti-inflammatory agents, as described above, can also
be incorporated into the compositions of the invention. Suitable
pharmaceutically active compounds that may be used can be found in
Harrison's Principles of Internal Medicine.
[0420] A pharmaceutical composition of the invention is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include parenteral, e.g.,
intravenous, intradermal, subcutaneous, oral (e.g., inhalation),
transdermal (topical), transmucosal, and rectal administration.
Solutions or suspensions used for parenteral, intradermal, or
subcutaneous application can include the following components: a
sterile diluent such as water for injection, saline solution, fixed
oils, polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or sodium
bisulfite; chelating agents such as ethylenediaminetetraacetic
acid; buffers such as acetates, citrates or phosphates and agents
for the adjustment of tonicity such as sodium chloride or dextrose.
pH can be adjusted with acids or bases, such as hydrochloric acid
or sodium hydroxide. The parenteral preparation can be enclosed in
ampoules, disposable syringes or multiple dose vials made of glass
or plastic.
[0421] Pharmaceutical compositions suitable for injection include
sterile aqueous
[0422] solutions (where water soluble) or dispersions, or sterile
powders for the extemporaneous preparation of sterile injectable
solutions or dispersions. For intravenous administration, suitable
carriers include physiological saline, bacteriostatic water,
Cremophor EI.TM. (BASF, Parsippany, N.J.) or phosphate buffered
saline (PBS). In all cases, the pharmaceutical composition must be
sterile and should be fluid to the extent that easy syringability
exists. It must also be stable under the conditions of manufacture
and storage and must be preserved against the contaminating action
of microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (for example, glycerol, propylene glycol, and
liquid polyetheylene glycol, and the like), and suitable mixtures
thereof. The proper fluidity can be maintained, for example, by the
use of a coating such as lecithin, by the maintenance of the
required particle size in the case of dispersion and by the use of
surfactants. Prevention of the action of microorganisms can be
achieved by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, ascorbic acid,
thimerosal, and the like. In many cases, it will be preferable to
include isotonic agents, for example, sugars, polyalcohols such as
mannitol, sorbitol, or sodium chloride in the composition.
Prolonged absorption of the injectable compositions can be brought
about by including in the composition an agent which delays
absorption, for example, aluminum monostearate and gelatin.
[0423] Sterile injectable solutions can be prepared by
incorporating the compound of the invention in the required amount
in an appropriate solvent with one or a combination of the
ingredients enumerated above, as needed, followed by filtered
sterilization. Generally, dispersions are prepared by incorporating
the compound into a sterile vehicle which contains a basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum drying and freeze-drying which yields a
powder of the compound plus any additional desired ingredient from
a previously sterile-filtered solution thereof.
[0424] Oral compositions generally include an inert diluent or an
edible carrier. They can be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the compound of the invention can be incorporated
with excipients and used in the form of tablets, troches, or
capsules. Oral compositions can also include an enteric coating.
Oral compositions can also be prepared using a fluid carrier for
use as a mouthwash, wherein the compound in the fluid carrier is
applied orally and swished and expectorated or swallowed.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition. The tablets,
pills, capsules, troches and the like can contain any of the
following ingredients, or compounds of a similar nature: a binder
such as microcrystalline cellulose, gum tragacanth or gelatin; an
excipient such as starch or lactose, a disintegrating agent such as
alginic acid, Primogel, or corn starch; a lubricant such as
magnesium stearate or Sterotes; a glidant such as colloidal silicon
dioxide; a sweetening agent such as sucrose or saccharin; or a
flavoring agent such as peppermint, methyl salicylate, or orange
flavoring.
[0425] For administration by inhalation, the compounds of the
invention are delivered in the form of an aerosol spray from a
pressured container or dispenser which contains a suitable
propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
[0426] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration,
detergents, bile salts, and fusidic acid derivatives. Transmucosal
administration can be accomplished through the use of nasal sprays
or suppositories. For transdermal administration, the compounds of
the invention are formulated into ointments, salves, gels, or
creams as generally known in the art.
[0427] The present pharmaceutical compositions can also be prepared
in the form of suppositories (with conventional suppository bases
such as cocoa butter and other glycerides) or retention enemas for
rectal delivery.
[0428] In one embodiment, the compounds are prepared with carriers
that will protect the compound against rapid elimination from the
body, such as a controlled release formulation, including implants
and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art. The materials can also be
obtained commercially from Alza Corporation and Nova
Pharmaceuticals, Inc. Liposomal suspensions can also be used as
pharmaceutically acceptable carriers. These can be prepared
according to methods known to those skilled in the art, for
example, as described in U.S. Pat. No. 4,522,811, U.S. Pat. No.
5,455,044and U.S. Pat. No. 5,576,018, and U.S. Pat. No. 4,883,666,
the contents of all of which are incorporated herein by
reference.
[0429] The compounds of the invention can also be incorporated into
pharmaceutical compositions which allow for the sustained delivery
of the compounds to a subject for a period of at least several
weeks to a month or more. Such formulations are described in
published PCT application no. WO 02/74247, incorporated herein by
reference.
[0430] It is especially advantageous to formulate oral or
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the subject to be treated; each unit containing a
predetermined quantity of a compound of the invention calculated to
produce the desired therapeutic effect in association with the
required pharmaceutical carrier. The specification for the unit
dosage forms of the invention are dictated by and directly
dependent on the unique characteristics of the compound and the
particular therapeutic effect to be achieved, and the limitations
inherent in the art of compounding such compounds for the treatment
of individuals.
[0431] This invention is further illustrated by the following
examples, which should not be construed as limiting. The contents
of all references, patents, patent applications cited throughout
this application are incorporated herein by reference. It should be
understood that the use of any of the compounds described herein
are within the scope of the present invention and are intended to
be encompassed by the present invention and are expressly
incorporated herein for all purposes.
EXAMPLES
Example 1
General protocol for synthesis of substituted
1-(4-(phenylthio)phenyl)ethanone
[0432] A mixture of substituted mercaptophenol (1.0 equiv),
substituted 1-(4-fluorophenyl)ethanone 1 (1.0 equivalents), and
K.sub.2CO.sub.3 (2.0 equiv) in DMF was heat at 50.degree. C. for
3-18 hours under a nitrogen atmosphere. Benzyl bromide (1.0
equivalent) was then added, and the resulting mixture was stirred
for additional 3 hours at 60.degree. C. The mixture was allowed to
cool to room temperature, and then was diluted with ethyl acetate
(EtOAc) and washed with water (2 times), and brine (1 time). The
organic layer was dried with MgSO.sub.4 and concentrated under
reduced pressure. The product was purified by silica gel column
chromatography using the Combi-Flash system as required.
1-(4-(3-(benzyloxy)phenylthio)-2-chlorophenyl)ethanone (2a)
##STR00139##
[0434] The title compound was purified by silica gel column
chromatography using the Combi-Flash system (Hex:EtOAc) to give
4.10 g (70%) of a yellowish oil. Proton NMR and LC analyses
confirmed the desired product with purity greater than 95%. TLC
(1:4EtOAc:Hex), R.sub.f=0.6; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.47 (d, 1H, J=8.4 Hz), 7.29-7.43 (m, 6H), 7.19 (d, 1H,
J=2.0 Hz), 7.05-7.10 (m, 3H), 6.98-7.02 (m, 1H), 5.06 (s, 2H), 2.63
(s, 3H).
1-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)phenyl)ethanone
(2b)
##STR00140##
[0436] The title compound was purified by silica gel column
chromatography using the Combi-Flash system (Hex:EtOAc) to give
1.92 g (60%) of a yellowish oil. Proton NMR and LC analyses
confirmed the desired product with purity greater than 95%. TLC
(1:4 EtOAc:Hex), R.sub.f=0.6; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.02 (d, 1H, J=1.6 Hz), 7.81 (dd, 1H, J=8.4 Hz, J=1.6 Hz),
7.30-7.43 (m, 6H), 7.11-7.15 (m, 2H), 7.03-7.08 (m, 2H), 5.06 (s,
2H), 2.7=58 (s, 3H).
Example 2
General Protocol for Synthesis of Substituted phenyl-imidazole
Scaffold
[0437] To a solution of the substituted acetophenone 2 (1.0
equivalent) in MeOH/CH.sub.2Cl.sub.2 (1:4) under a nitrogen
atmosphere was added tetrabutyl ammonium tribromide
(Bu.sub.4NBr.sub.3) (1.0 equivalents). The reaction mixture was
stirred at room temperature for 2-18 hours. The reaction was
monitored by TLC or LC to confirm completion. The solvent removed
in vacuo and the crude product was either carried forward without
further purification or was purified by silica gel column
chromatography using the Combi-Flash system (Hex:EtOAc).
[0438] A mixture of the desired bromo-acetophenone 3 (from last
step, 1.0 equivalent), Boc-.alpha.-MeSer (1.0 equiv), and
Cs.sub.2CO.sub.3 (0.6 equivalent) was stirred in DMF for 1-2 hours.
The reaction mixture was diluted with EtOAc and washed with water
(2.times.), and saturated brine (1.times.) to remove excess DMF and
CsBr. The organic layer was dried over anhydrous MgSO.sub.4 and the
solvent was removed at reduced pressure. TLC generally showed a
spot to spot conversion of the starting material to product
ester.
[0439] To the thus-obtained ester was then added excess ammonium
acetate (10 equivalents), and the mixture was suspended in toluene
and refluxed for 3-6 hours using a Dean-Stark apparatus. The
mixture was diluted with EtOAc and washed with water (2.times.),
and brine (1.times.). The organic layer was dried over anhydrous
MgSO.sub.4 and the solvent was removed at reduced pressure. The
product was purified by silica gel column chromatography using the
Combi-Flash system (Hex:EtOAc).
(R)-tert-butyl
2-(4-(4-(3-(benzyloxy)phenylthio)-2-chlorophenyl)-1H-imidazol-2-yl)-1-hyd-
roxypropan-2-ylcarbamate (4a)
##STR00141##
[0441] The title compound was purified by silica gel column
chromatography using the Combi-Flash system (Hex:EtOAc) as yellow
solid in 27% (120 mg). LC-MS analyses confirmed the desired product
with purity greater than 90%. TLC (1:1 EtOAc:Hex), R.sub.f=0.3; MS
(ESI, M+H.sup.+)=566.05
(R)-tert-butyl
2-(4-(4-(3-(benzyloxy)phenylthio)-S-(trifluoromethyl)phenyl)-1H-inidazol--
2-yl)-1-hydroxypropan-2-ylcarbamate (4b)
##STR00142##
[0443] The title compound was purified by silica gel column
chromatography using the Combi-Flash system (Hex:EtOAc) to give 320
mg (80%) as a yellow solid. LC-MS analyses confirmed the desired
product with purity greater than 95%. TLC (1:1 EtOAc:Hex),
R.sub.f=0.3; MS (ESI, M+H.sup.+)=600.07
Example 4
General Protocol for Deprotection of the Amino Group
[0444] To a solution of the Boc-protected precursor 4 (1.0 equiv)
in CH.sub.2Cl.sub.2 was added TFA (25% by volume). The reaction
mixture was stirred at room temperature for 1-2 hours then
evaporated to dryness under reduced pressure to afford the desired
product. The final product was purified by reverse-phase
preparative HPLC of the corresponding TFA salt in 60-70% yield.
(R)-2-amino-2-(4-(4-(S-(benzyloxy)phenylthio)-2-chlorophenyl)-1H-imidazol--
2-yl)propan-1-ol (5a)
##STR00143##
[0446] The title compound was purified as the TFA salt by reverse
phase preparative HPLC, followed by lyophilization to give the 14
mg of the product as a white solid (60%). MS (ESI,
M+H.sup.+)=461.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.42
(br s, 2H), 8.13 (br s, 1H), 7.81 (br s, 1H), 7.28-7.42 (m, 7H),
6.90-7.02 (m, 3H), 5.08 (s, 2H), 3.77 (d, 1H, J=10.4 Hz), 3.66 (d,
1H, J=10.4 Hz), 1.56 (s, 3H).
(R)-2-amino-2-(4-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)phenyl)-1-
H-imidazol-2-yl)propan-1-ol (5b)
##STR00144##
[0448] The title compound was purified as the TFA salt by reverse
phase preparative HPLC, followed by lyophilization to give the 45
mg of the product as a white solid (70%). MS (ESI,
M+H.sup.+)=500.06; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.44
(br s, 3H), 8.26 (br s, 1H), 7.97 (d, 1H, J=7.6 Hz), 7.93 (br s,
1H), 7.27-7.43 (m, 6H), 6.98 (dd, 1H, J=8.4 Hz, J=2.4 Hz),
6.82-6.89 (m, 2H), 5.70 (br s, 1H), 5.06 (s, 2H), 3.75 (d, 1H,
J=10.8 Hz), 3.65 (d, 1H, J=10.8 Hz), 1.54 (s, 3H).
Example 5
Preparation of Phenyl-thiadiazole Analogs
4-Methoxybenzyl
4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)benzoate (7a)
##STR00145##
[0450] A suspension of 4-methoxybenzyl
4-fluoro-3-(trifluoromethyl)benzoate (602 mg, 1.83 mmol), potassium
carbonate (555 mg, 4.03 mmol) and 3-mercaptophenol (241 mg, 96%,
1.83 mmol) in DMF (10 mL) was stirred at 50.degree. C. for
overnight. Benzyl bromide (638 mL, 3.66 mmol) was then added
drop-wise followed by raising the temperature to 65.degree. C. for
3 hours. The reaction was cooled to room temperature and diluted
with ethyl acetate (30 mL) and washed with water (10 mL) followed
by brine (2.times.10 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under vacuum to provide a crude
product, which was further purified on a silica gel column, washed
with ethyl acetate/hexanes (0-20%, v/v) and afforded the title
compound (717 mg, 75%). TLC (EtOAc:Hex, 1:5), R.sub.f=0.35; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.29 (d, 1H, J=1.6 Hz), 7.89 (dd,
1H, J=8.4 Hz, J=1.6 Hz), 7.39-7.29 (m, 8H), 7.10 (dd, 2H, J=7.4 Hz,
J=1.6 Hz), 7.02 (t, 2H, J=8.0 Hz), 6.90 (dt, 2H, J=8.8 Hz, J=2 Hz),
5.28 (s, 2H), 5.03 (s, 2H), 3.80 (s, 3H).
4-Methoxybenzyl 4-(3-(benzyloxy)phenylthio)-2-chlorobenzoate
(7b)
##STR00146##
[0452] The title compound was prepared analogously to 7a by using
4-methoxybenzyl 2-chloro-4-fluorobenzoate as a starting material.
TLC (EtOAc:Hex, 1:5), R.sub.f=0.25; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.71 (d, 2H, J=8.0 Hz), 7.41-7.28 (m, 7H), 7.20
(d, 1H, J=2.0 Hz), 7.07-6.98 (m, 4H), 6.91-6.88 (dt, 2H, J=8.8 Hz,
J=2.4 Hz), 5.27 (s, 2H), 5.04 (s, 2H), 3.80 (s, 3H).
4-(3-(Benzyloxy)phenylthio)-3-(trifluoromethyl)benzohydrazide
(8a)
##STR00147##
[0454] A mixture of 4-methoxybenzyl
4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)-benzoate (7a, 397
mg), hydrazine (0.6 mL) and ethylene glycol (10 mL) was heated at
140.degree. C. with stirring for 2 h. Cooled to room temperature,
the reaction was poured into cold water (10 mL) and the title
compound was collected as white crystal-like solid (285 mg, 90%).
MS (ESI, MH.sup.+)=419.03.
4-(3-(Benzyloxy)phenylthio)-2-chlorobenzohydrazide (8b)
##STR00148##
[0456] The title compound was prepared analogously to 8a by using
4-methoxybenzyl 4-(3-(benzyloxy)phenylthio)-2-chlorobenzoate (7b)
as a starting material in 71% yield. MS (ESI, MH.sup.+)=385.06.
(R)-t-Butyl
4-(2-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)benzoyl)hydrazine-ca-
rbonyl)-2,2,4-trimethyloxazolidine-3-carboxylate (10a)
##STR00149##
[0458] To a solution of
(R)-3-Boc-2,2,4-trimethyloxazolidine-4-carboxylic acid (60 mg, 0.23
mmol) in CH.sub.2Cl.sub.2/DMF (2:1, 3 mL) was added HATU (87 mg,
0.27 mmol) and DIEA (0.2 mL, 1.15 mmol). The resultant was stirred
at room temperature for 10 min and then was added
4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)benzohydrazide (8a,
96 mg, 0.23 mmol). The reaction was continuously stirred for
another 30 min and then directly chromatographed on a silica gel
column eluted with ethyl acetate/hexane (0.about.30%, v/v) to
afford the title compound (145 mg, 95%). TLC (EtOAc:Hex, 1:5),
R.sub.f=0.20; MS (ESI, MH.sup.+)=659.85; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.10 (d, 1H, J=1.6 Hz), 7.66 (dd, 1H, J=8.0 Hz,
J=1.6 Hz), 7.41-7.31 (m, 6H), 7.11-7.09 (m, 2H), 7.06-7.03 (m, 2H),
5.05 (s, 2H), 4.60-4.40 (br s, 1H), 3.75 (br s, 1H), 1.58 (s, 3H),
1.51 (s, 9H).
(R)-t-Butyl
4-(2-(4-(3-(benzyloxy)phenylthio)-2-chlorobenzoyl)hydrazinecarbonyl)-2,2,-
4-trimethyloxazolidine-3-carboxylate (10b)
##STR00150##
[0460] The title compound was prepared analogously to 10a by using
4-(3-(Benzyloxy)phenylthio)-2-chlorobenzohydrazide (8b) as a
starting material in 90% yield. TLC (EtOAc:Hex, 1:5), R.sub.f=0.15;
MS (ESI, MH.sup.+)=625.91; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.71 (d, 1H, J=4.8 Hz), 7.42-7.30 (m, 6H), 7.18 (d, 1H,
J=2.0 Hz), 7.10 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.08-7.06 (m, 2H),
7.02-7.00 (m, 1H), 5.05 (s, 2H), 4.60-4.30 (br, 1H), 3.77 (br, 1H),
1.58 (s, 3H), 1.51 (s, 9H).
(R)-t-Butyl
4-(5-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)phenyl)-1,3,4-thiadi-
azol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate (11a)
##STR00151##
[0462] The suspension of 10a (145 mg, 0.22 mmol) and Lawesson's
reagent (266 mg, 0.66 mg) in toluene (5 mL) was heated at
85.degree. C. for 2 h with stirring. After cooling down to room
temperature, the supernatant was directly chromatographed on a
silica gel column eluted with ethyl acetate/hexane (0-15%) to
afford the title compound (123 mg, 85%). MS (ESI,
MH.sup.+)=658.16.
(R)-t-Butyl
4-(5-(4-(3-(benzyloxy)phenylthio)-2-chlorophenyl)-1,3,4-thiadiazol-2-yl)--
2,2,4-trimethyloxazolidine-3-carboxylate (11b)
##STR00152##
[0464] The title compound was prepared analogously to 11a by using
(R)-t-Butyl
4-(2-(4-(3-(benzyloxy)phenylthio)-2-chlorobenzoyl)hydrazinecarbonyl)-2,2,-
4-trimethyloxazoli-dine-3-carboxylate (10b) as a starting material
in 83% yield. MS (ESI, MH.sup.+)=624.14
(S)-2-Amino-2-(5-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)phenyl)-1-
,3,4-thiadiazol-2-yl)propanol (12a)
##STR00153##
[0466] A solution of (R)-t-Butyl
4-(5-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)-phenyl)-1,3,4-thiad-
iazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate (11a, 123 mg,
0.18 mmol) in methanol (7 mL) was heated at 70.degree. C. for 2
hours. After cooling to room temperature, water (2 mL) was added
and the reaction mixture was directly injected to preparative HPLC
for purification with 30-90% acetonitrile-H.sub.2O (0.1% TFA) in 15
minutes of gradient time as mobile phase to afford the title
compound (97 mg, 72%) as bis-TFA salt. MS (ESI, MH.sup.+)=518.02;
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.89 (br, 3H), 8.30 (s, 1H),
8.12 (d, 1H, J=8.4 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.43 (d, 2H, J=8.8
Hz), 7.37 (t, 2H, J=7.2 Hz), 7.33 (d, 1H, J=6.8 Hz), 7.26 (d, 1H,
J=8.8 Hz), 7.20-7.16 (m, 2H), 7.14 (d, 1H, J=8.0 Hz), 6.16 (br s,
1H), 5.14 (s, 2H), 3.84 (dd, 1H, J=10.8 Hz, J=3.2 Hz), 3.77 (dd,
1H, J=10.8 Hz, J=3.2 Hz), 1.71 (s, 3H).
(S)-2-Amino-2-(5-(4-(3-(benzyloxy)phenylthio)-2-chlorophenyl)-1,3,4-thiadi-
azol-2-yl)propanol (12b)
##STR00154##
[0468] The title compound was prepared analogously to 12a by using
(R)-t-Butyl
4-(5-(4-(3-(benzyloxy)phenylthio)-2-chlorophenyl)-1,3,4-thiadiazol-2-yl)--
2,2,4-trimethyloxazoli-dine-3-carboxylate (11b) as a starting
material in 77% yield (bis-TFA salt). MS (ESI, MH.sup.+)=484.01;
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.50 (br, 1H), 8.12 (d, 1H,
J=8.0 Hz), 7.46-7.42 (m, 4H), 7.38 (t, 2H, J=7.2 Hz), 7.33-7.28 (m,
2H), 7.19 (s, 1H), 7.15 (t, 2H, J=7.2 Hz), 6.06 (br s, 1H), 5.15
(s, 2H), 3.84 (dd, 1H, J=10.8 Hz, J=5.2 Hz), 3.76 (dd, 1H, J=10.8
Hz, J=5.2 Hz), 1.70 (s, 3H).
Example 6
General Method for Phosphate Synthesis
[0469] The general method for the synthesis of the desired
phosphates in illustrated in scheme 3. To a solution of unprotected
or Boc-protected amino alcohol (1.0 equiv) in dry CH.sub.2Cl.sub.2
at room temperature was added excess diethyl chlorophosphate
(5.0-20.0 equiv) and triethylamine (5.0-30.0 equiv) and the
reaction was stirred at room temperature for 12-18 hours. The crude
was then loaded onto a silica gel column chromatography, as is, to
purify the desired phospho-diester. The phopho-diester intermediate
was reacted with excess bromotrimethylsilane (10.0-20.0 equiv) in
dry CH.sub.2Cl.sub.2 at room temperature, under an atmosphere of
nitrogen; over a period of 5-8 hours afforded the final phosphate
which was purified by reverse-phase preparative HPLC.
##STR00155##
(R)-2-amino-2-(4-(4-(3-(benzyloxy)phenylthio)-2-chlorophenyl)-1H-imidazol-
-2-yl)propyl dihydrogen phosphate
##STR00156##
[0471] The final product was purified by reverse phase preparative
HPLC, then lyophilized to dryness to obtain TFA salt of the
product. The product was obtained as a white solid in 24% (10 mg)
yield from the alcohol precursor. MS (ESI, M+H.sup.+)=546.3.
(R)-2-amino-2-(4-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)phenyl)-1-
H-imidazol-2-yl)propyl dihydrogen phosphate
##STR00157##
[0473] The final product was purified by reverse phase preparative
HPLC, then lyophilized to dryness to obtain TFA salt of the
product. The product was obtained as a white solid in 47% (45 mg)
yield from the alcohol precursor. MS (ESI, M+H.sup.+)=580.07.
(S)-2-Amino-2-(5-(4-(3-(benzyloxy)phenylthio)-3-(trifluoromethyl)phenyl)-1-
,3,4-thiadiazol-2-yl)propyl dihydrogen phosphate
##STR00158##
[0475] Yield: 6.8% (the low yield is due to the breakdown of the
benzyl group in the deprotection step), MS (ESI, MH.sup.+)=597.98,
purity 99% by HPLC.
(S)-2-Amino-2-(5-(4-(3-(benzyloxy)phenylthio)-2-chlorophenyl)-1,3,4-thiadi-
azol-2-yl)propyl dihydrogen phosphate
##STR00159##
[0477] Yield: 6.5% (the low yield is due to the breakdown of the
benzyl group in the deprotection step), MS (ESI, MH.sup.+)=563.97,
purity 99% by HPLC.
Example 7
General Synthetic Strategy for Synthesis of phenyl-imidazole
Analogs
[0478] The general approach for synthesis of various
biaryl-thio-ethers 6 and 7 is described in Scheme 4. Reaction of
substituted 3-mercaptophenol with substituted
1-fluoro-4-nitrobenzene 1 and benzyl bromide afforded the
thio-ether-nitrobenzene intermediate 2. The thio-ether-nitrobenzene
2 was then converted to the thio-ether-aniline 3 using SnCl.sub.1.
Acylation of the thio-ether-aniline 3 with oxazolidine-carboxylic
acid 4 under acid chloride condition afforded the amide 5.
Deprotection of the protecting groups with para-toluenesulfonic
acid (PTSA) provided the alcohol 6 in good yield. Alcohol 6 was
then converted to phosphate 7 in two steps.
##STR00160##
Example 8
General Protocol for Synthesis of Substituted
1-(4-(phenylthio)phenyl)ethanone
[0479] A mixture of substituted mercaptophenol (1.0 equivalent),
substituted 1-(4-fluorophenyl)ethanone 1 (1.0 equivalent), and
K.sub.2CO.sub.3 (2.0 equivalents) in DMF under nitrogen atmosphere
was heat at 50.degree. C. for 3-18 hours. To the reaction was then
added BnBr (if necessary, 1.0 equivalent) and stirred for
additional 3 hours at 60.degree. C. The reaction cooling to room
temperature then diluted with EtOAc and washed with H.sub.2O
(2.times.); saturated NaCl (1.times.), dried with MgSO.sub.4. The
organic layer was then concentrated under reduced pressure. The
product was purified by silica gel column chromatography using the
Combi-Flash system as required.
(3-(Benzyloxy)phenyl)(3-chloro-4-nitrophenyl)sulfane (2a)
##STR00161##
[0481] The product was purified by silica gel column chromatography
using the Combi-Flash system (Hex:EtOAc) as yellowish oil in 37%
(1.10 g). Proton NMR and LC analyses confirmed the desired product
with purity greater than 95%. TLC (1:4 EtOAc:Hex), R.sub.f=0.6;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, 1H, J=8.4 Hz),
7.31-7.43 (m, 6H), 7.20 (d, 1H, J=2.0 Hz), 7.05-7.10 (m, 3H), 7.02
(dd, 1H, J=8.4 Hz, J=1.6 Hz), 5.08 (s, 2H).
4-(3-(Benzyloxy)phenylthio)-2-chloroaniline (3a)
##STR00162##
[0483] To a mixture of the nitro intermediate 2a (1.05 g, 1.0
equivalent) and SnCb (2.68 g, 5.0 equivalents) was added EtOH/EtOAc
(1:1, 30 mL) then heated at 80.degree. C. for 2 hours. The solvent
was removed in vacuo and the product was purified by silica gel
column chromatography using Combi-Flash system (Hex:EtOAc). The
product was obtained as colorless oil in 88% (0.85 g) yield. TLC
(1:4 EtOAc:Hex), R.sub.f=0.4; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.41 (d, 1H, J=2.0 Hz), 7.28-7.40 (m, 6H), 7.20 (dd, 1H,
J=8.0 Hz, J=2.0 Hz), 7.14 (t, 1H, J=7.4 Hz), 6.71-6.80 (m, 3H),
4.98 (s, 2H), 4.21 (br s, 2H).
(R)-tert-Butyl
4-(4-(3-(benzyloxy)phenylthio)phenylcarbamoyl)-2,2,4-trimethyloxazolidine-
-3-carboxylate (5a)
##STR00163##
[0485] To a solution of
(S)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic
acid 4 (200 mg, 1.0 equivalent) in dry THF (6 mL) was added oxalyl
chloride (1.2 equivalents) and catalytic amount of DMF (2 drops).
The reaction was allowed to stir at room temperature for 20
minutes. To the reaction mixture was then added the aniline 3a (1.0
equivalent). The reaction was allowed to stir overnight. The
solvent removed in vacuo and the crude product was purified by
silica gel column chromatography using Combi-Flash system
(Hex:EtOAc). The product was obtained as a colorless oil in 45%
(200 mg) yield. TLC (1:4 EtOAc:Hex), R.sub.f=0.6; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.42 (d, 1H, J=8.4 Hz), 7.24-7.42 (m, 8H),
7.21 (t, 1H, J=8.4 Hz), 6.80-6.92 (m, 2H), 5.01 (s, 2H), 3.89 (br
s, 2H), 1.32-1.84 (m, 18H).
(S)-2-Amino-N-(4-(3-(benzyloxy)phenylthio)phenyl)-3-hydroxy-2-methylpropan-
amide (6a)
##STR00164##
[0487] A solution of oxazolidine-amide 5a (200 mg) and PTSA
mono-hydrate (652 mg, 10 equivalents) in MeOH (10 mL) was refluxed
for overnight. The solvent was removed in vacuo and the product was
purified by reverse phase preparative HPLC, then lyophilized to
dryness to obtain TFA salt of the product. The solvent was obtained
as a white solid in 65% yield (124 mg). MS (ESI, M+H.sup.+)=443.09;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.92 (s, 1H), 8.20 (s,
3H), 7.26-7.51 (m, 9H), 7.93-7.04 (m, 3H), 5.97 (br s, 1H), 5.09
(br s, 2H), 3.93 (dd, 1H, J=11.2, Hz, J=1.2 Hz), 3.69 (dd, 1H,
J=11.2 Hz, J=1.2 Hz), 1.51 (s, 3H).
Example 9
General Method for Phosphate Synthesis
[0488] The general method for synthesis of the desired phosphates
in illustrated in scheme 1. To a solution of amino alcohol 6a (1.0
equivalent) in dry CH.sub.2Cl.sub.2 at room temperature was added
excess diethyl chlorophosphate (10.0 equivalents) and triethylamine
(20.0 equivalents) and the reaction stirred for 12-18 hours. The
solvent removed in vacuo and the crude phopho-diester intermediate
was reacted with excess bromotrimethylsilane (20.0 equivalents) in
dry CH.sub.2Cl.sub.2 at room temperature over a period of 5 hours
to afford the final phosphate which was purified by reverse-phase
preparative HPLC.
(S)-2-Amino-3-(4-(3-(benzyloxy)phenylthio)phenylamino)-2-methyl-3-oxopropy-
l dihydrogen phosphate 7a
##STR00165##
[0490] The final product was purified by reverse phase preparative
HPLC, then lyophilized to dryness to obtain TFA salt of the
product. The product was obtained as a white solid in 23% (10.4 mg)
yield from the alcohol precursor. MS (ESI, M+H.sup.+)=523.03;
* * * * *